Useful aroyl pyrrole heteroaryl methanones and methanols

ABSTRACT

This invention is directed to aroyl pyrrole heteroaryl methanone and methanol compounds pharmaceutically useful as agents for treating or modulating a central nervous system disorder and methods for treating or modulating a central nervous system disorder.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. provisional applicationSer. No. 60/343,768 filed Dec. 27, 2001, the contents of which arehereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to compounds useful as agents for treating ormodulating a central nervous system disorder. More particularly, thisinvention relates to aroyl pyrrole heteroaryl methanone and methanolcompounds useful as agents for treating or modulating a central nervoussystem disorder.

BACKGROUND OF THE INVENTION

The conditions grouped under the term “central nervous system disorder”constitute an area of continuing medical need. Such conditions includethose disorders associated with neuropathic pain, inflammatory pain,inflammation-related pain or epilepsy.

Sodium channels have been suggested to play a role in (and sodiumchannel blockers to be useful in treating) many disorders of the centralnervous system (Madge, D., Sodium Channels: Recent Developments andTherapeutic Potential, Annual Reports in Medicinal Chemistry, 1998, 33,51-60, 56). The majority of the compounds studied to date show somepotential in more than one of these disorders; very few compounds withselective anticonvulsant, analgesic or neuroprotective activity havebeen identified (Madge, D., p 56).

In the past few years a much better understanding of sodium channels anddrugs interacting with them has been developed (Anger, T., Madge, D.,Mulla M. and Riddall, D., Medicinal Chemistry of Neuronal Voltage-GatedSodium Channel Blockers, Journal of Medicinal Chemistry, 2001, 44(2),115-137). It has become clear that a number of drugs having an unknownmechanism of action actually act by modulating sodium channelconductance, including local anesthetics, class I antiarrhythmics andanticonvulsants (Anger, T., et al., p 123). Neuronal sodium channelblockers have found application with their use in the treatment ofepilepsy (phenytoin and carbamazepine, long used as anticonvulsants butwithout a clear understanding of their mechanism of action),neuroprotection (as a result of ischemic stroke and other brain trauma),preventing neurodegeneration (such as in the treatment of amyotrophiclateral sclerosis by, primarily, sodium channel blockage) and inreducing neuropathic pain (as a result of trigeminal neuralgia, diabeticneuropathy, post-herpetic neuralgia, neuroma pain and phantom limbsyndrome) (Anger, T., et al., pp 124, 126, 129).

Neuropathic pain and other chronic and debilitating condition-associatedpain syndromes are all associated with changes in neuronal excitability(Brau M. E., et al, Effect of drugs used for neuropathic pain managementon tetrodotoxin-resistant Na(+) currents in rat sensory neurons,Anesthesiology, 2001, January, 94(1), 137-44; Siddall P. J. and LoeserJ. D., Pain following spinal cord injury, Spinal Cord, 2001, Feb, 39(2),63-73; Kontinen V. K., et al, Electrophysiologic evidence for increasedendogenous gabanergic but not glycinergic inhibitory tone in the ratspinal nerve ligation model of neuropathy, Anesthesiology, 2001,February, 94(2), 333-9).

Various anti-epileptic drugs (AEDs) that stabilize neuronal excitabilityare effective in neuropathic pain (Johannessen C. U., Mechanisms ofaction of valproate: a commentatory, Neurochem. Int., 2000,August-September, 37(2-3), 103-110 and Magnus L., Nonepileptic uses ofgabapentin, Epilepsia, 1999, 40 Suppl 6, S66-72; Nadin Attal, et al.,Effects of Gabapentin on the Different Components of Peripheral andCentral Neuropathic Pain Syndromes: A Pilot Study, Fr. Eur. Neurol.1998, 40(4), 191-200.

In particular, neuropathic pain is defined as pain caused by aberrantsomatosensory processing in the peripheral or central nervous system andincludes neuropathic pain resulting from chronic or debilitatingconditions (such as painful diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain,multiple sclerosis-associated pain, neuropathies-associated pain (suchas in idiopathic or post-traumatic neuropathy and mononeuritis),HIV-associated neuropathic pain, cancer-associated neuropathic pain,carpal tunnel-associated neuropathic pain, spinal cord injury-associatedpain, complex regional pain syndrome, fibromyalgia-associatedneuropathic pain, lumbar and cervical pain, reflex sympathic dystrophy,phantom limb syndrome and other chronic and debilitatingcondition-associated pain syndromes), sympathetically maintained pain orcluster and migraine headache-associated pain; pain associated withcancer, fibromyalgia, back disorders or migraine and chronic headache,adiposis dolorosa and burn pain, central pain conditions followingstroke, thalamic lesions or multiple sclerosis or pain resulting fromdamage to the peripheral or central nervous system (after amputation,paraplegia, herpes or as a result of diabetic polyneuropathy).

An increase in sodium channel expression or activity is observed inseveral animal models of inflammatory pain. Expression of α-SNS mRNA andtetrodotoxin-resistant sodium current in small DRG neurons increasedfollowing injection of carrageenan into the plantar surface of the rathindpaw (Tanaka M., NeuroReport, 1998, 9, 967-972). Similarly, theinduction of chronic inflammation with the injection of CompleteFreund's Adjuvant was followed by the development of inflammatorythermal hypersensitivity and increased sodium channel staining (Gould H.J., et al., Brain Res., 1998, 802 (1), 69-74; Gould H. J., et al., BrainRes., 1999, 824, 296-299). Antisense (but not sense or missense) to thePN3 sodium channel prevented the development of mechanical flexionreflex hyperalgesia following the administration of the inflammatoryagent PGE₂ (Khasar S. G., et al., Neurosci. Lrs., 1998, 256, 17-20).

Patent references describe compounds as sodium channel modulators orantagonists for use in treating or modulating central nervous systemdisorders in a number of in vitro and in vivo models.

U.S. Pat. No. 6,288,278 describes 3-amino-3-arylpropan-1-ol derivativesas sodium channel blockers in a BTX-binding assay (S. W. Postma & W. A.Catterall, Mol. Pharmacol., 1984 25, 219-227) and methods for use aslocal anesthetic, antiarrhythmic, antiemetic and nootropic (neurotropic)agents and as agents for the treatment/therapy of cardiovasculardiseases, urinary incontinence, diarrhea, pruritus, alcohol or drugdependency and inflammation.

U.S. Pat. No. 6,288,123 describes disubstituted guanidine compounds asmodulators or inhibitors for release of neurotransmitters such asglutamate from ischemic neuronal cells by blocking presynaptic calciumand/or sodium channels in an inhibition of glutamate release assay, inan inhibition of ⁴⁵Ca uptake through presynaptic calcium channels assay,in an inhibition of ⁴⁵Ca uptake through L-type(dihydropyridine-sensitive) calcium channels assay, in an inhibition of[¹⁴C]-guanidinium uptake through Type II neuronal voltage-activatedsodium channels assay, in an in vivo anticonvulsant/audiogenic seizuresD6A/2 mouse model and methods for use in the treatment and/orprophylaxis of neurological conditions such as epilepsy,neurodegenerative conditions and diseases (such as Parkinson's disease,Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer'sdisease, Down's Syndrome, Korsakoffs disease, olivopontocerebellaratrophy, HIV-induced dementia and blindness or multi- infarct dementia)and nerve cell death (as a result of hypoxia, hypoglycemia, brain orspinal chord ischemia, brain or spinal chord trauma or global cerebralischemia (as a result of stroke, heart attack, drowning or carbonmonoxide poisoning)); for use in the treatment of hypertension, cardiacarrhythmias or angina pectoris, endocrine disorders (such as acromegalyand diabetes insipidus) and chronic pain (including use as a localanesthetic); and, for use in the treatment of diseases in which thepathophysiology of the disorder involves excessive or otherwiseinappropriate (e.g., hypersecretory) cellular secretion (e.g., secretionof an endogenous substance such as a catecholamine, a hormone or agrowth factor).

U.S. Pat. No. 6,281,211 describes semicarbazide compounds as sodiumchannel blockers in a dissociated hippocampal neuronelectrophysiological assay, in a neuronal voltage-dependent in a ratforebrain membrane assay, in HEK-293 cells stably expressing hSkM 1sodium channels, in a [³H]BTX-B assay and in a mouse maximalelectroshock-induced seizure (MES) model and methods for treating,preventing or ameliorating neuronal loss (associated with stroke, globaland focal ischemia, CNS trauma, hypoglycemia, surgery and spinal cordtrauma), for the treatment or prevention of neurodegenerative conditions(such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS),Parkinson's disease, anxiety, convulsions, glaucoma, migraine headacheand muscle spasm), as antimanic depressants, as local anesthetics, asantiarrhythmics, as anticonvulsants, as agents for the treatment orprevention of diabetic neuropathy and for the treatment of pain (acute,chronic and surgical pain, neuropathic pain and migraine headache).

U.S. Pat. No. 6,265,405 describes 5-amino triazine derivatives as sodiumchannel blockers in a whole-cell (recombinant human brain type IIA Na⁺channel expressed in Chinese hamster ovary cells) voltage-clamp assay,as anticonvulsants in a rat MES model and a mouse pentylenetetrazolinfusion test, as agents for treating acute hyperalgesia andinflammation in a rat carrageenan paw model, as a neuroprotective agentin a MPTP-induced neurotoxicity model for Parkinson's disease andmethods for treating epilepsy (including simple partial seizures,complex partial seizures, secondary generalised seizures and generalizedseizures (further including absence seizures, myoclonic seizures, clonicseizures, tonic seizures, tonic clonic seizures and atonic seizures),bipolar disorder (alternatively known as manic depression; includingType I or II) and unipolar depression; for treating or preventing acutepain (musculoskeletal, post operative and surgical pain), chronic pain(inflammatory pain (from rheumatoid arthritis and osteoarthritis),neuropathic pain (from post herpetic neuralgia, trigeminal neuralgia andsympathetically maintained pain) and pain associated with cancer,fibromyalgia and migraine associated pain; for treating tinnitus,functional bowel disorders (non-ulcer dyspepsia, non-cardiac chest painand irritable bowel syndrome) and neurodegenerative diseases(Alzheimer's disease, ALS, motor neuron disease, Parkinson's disease,muscular sclerosis, macular degeneration and glaucoma), forneuroprotection (treating neurodegeneration following stroke, cardiacarrest, pulmonary bypass, traumatic brain injury and spinal cord injury)and for preventing or reducing dependence/tolerance/reverse tolerance toa dependence-inducing agent (such as opioids, CNS depressants,psychostimulants and nicotine).

U.S. Pat. No. 6,262,078 describes phenoxymethyl piperidine derivativesas sodium channel blockers in an in vitro rat vagus nerve assay(Kourtney and Stricharz, Local Anesthetics, Springer-Verlag, New York,1987) and as agents for the treatment of neuropathic pain in an in vivorat mechanical allodynia model (Kim and Chung, Pain, 1992, 50:355-363),in an in vivo rat acute and chronic cold allodynia, unilateralmononeuropathy, Chronic Constriction Injury model (Bennet and Xie, Pain,1988, 33:87-107), in an in vivo rat mechanical hyperalgesia model(Bennet and Xie, Pain, 1988, 33:87-107) and in an in vivo rat thermalhyperalgesia model and methods for treating peripheral neuropathies(trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy,glossopharyngeal neuralgia, lumbar and cervical radiculopathies, reflexsympathetic dystrophy and causalgia), neuropathy secondary to metastaticinfiltration, adiposis dolorosa and burn pain and central painconditions following stroke, thalamic lesions and multiple sclerosis.

U.S. Pat. No. 6,255,307 describes a class of phenyl pyrazine derivativesas sodium channel blockers and methods for treating epilepsy (includingsimple partial seizures, complex partial seizures, secondary generalisedseizures and generalized seizures (further including absence seizures,myoclonic seizures, clonic seizures, tonic seizures, tonic clonicseizures and atonic seizures), bipolar disorder (alternatively known asmanic depression; including Type I or II) and unipolar depression; fortreating or preventing acute pain (musculoskeletal, post operative andsurgical pain), chronic pain (inflammatory pain (from rheumatoidarthritis and osteoarthritis), neuropathic pain (from post herpeticneuralgia, trigeminal neuralgia and sympathetically maintained pain) andpain associated with cancer, fibromyalgia and migraine associated pain;for treating tinnitus, functional bowel disorders (non-ulcer dyspepsia,non-cardiac chest pain and irritable bowel syndrome) andneurodegenerative diseases (Alzheimer's disease, ALS, motor neurondisease, Parkinson's disease, muscular sclerosis, macular degenerationand glaucoma), for neuroprotection (treating neurodegeneration followingstroke, cardiac arrest, pulmonary bypass, traumatic brain injury andspinal cord injury) and for preventing or reducingdependence/tolerance/reverse tolerance to a dependence-inducing agent(such as opioids, CNS depressants, psychostimulants and nicotine).

U.S. Pat. No. 6,169,116 describes tetrahydro-naphthalenamines as sodiumchannel blockers in a rat hippocampal veratridine induced glutamateinhibition assay (modification of M. J. Leach et al., Epilepsia, 1986,27, 490-497 and Stroke, 1993, 24, 1063-1067 using exogenous glutamate)and in a veratridine binding assay (J. B. Brown, Journal ofNeuroscience, 1986, 6, 2064-2070), as agents for reducingischemia-induced neuronal damage and ensuing symptoms in a rat middlecerebral artery (MCA) occlusion model (A. Tamura et al., J. Cereb. BloodFlow Metabol., 1981, 1, 53-60; A. Sauter and M. Rudin, Stroke, 1986, 17,1228-1234) and methods for the treatment of any clinical conditioninvolving a component of cerebral anoxia, hypoxia or ischemia (ischemicdamage to grey and white matter) as a result of stroke, subarachnoidhemorrhage, brain and spinal cord injury/trauma, high intracranialpressure, mult-infarct dementia or vascular dementia, as the result ofany surgical procedure potentially associated with cerebral anoxia,hypoxia and/or ischemia (cardiac bypass, operations on extracerebralvessels), as the result of any pathology, disorder or clinical conditioninvolving glutamate release in their etiology (including psychiatricdisorders (such as schizophrenia, depression, anxiety, panic attacks,attention deficit and cognitive disorders or social withdrawal),hormonal conditions (such as excess GH (as in diabetes mellitus,angiopathy or acromegaly) or LH (as in prostate hypertrophy, menopausalsyndrome] secretion or corticosterone secretion in stress)), metabolicinduced brain damage (hypolycemia, non-ketotic hyperglycinaemia (glycineencephalopathy), sulphite oxidase deficiency or hepatic encephalopathyassociated with liver failure), emesis, spasticity, tinnitus, pain (as aresult of cancer or arthritis) and drug abuse and withdrawal (as aresult of the use of ethanol, opiate (including synthetics withopiate-like effects), cocaine, amphetamine, barbiturate and othersedatives and benzodiazepines)), as the result of any pathologyinvolving neuronal damage (including neurodegenerative disorders such asAlzheimer's, Huntington's or Parkinson's diseases, virus inducedneurodegeneration (including HIV), ALS, supra-nuclear palsy,olivoponto-cerebellar atrophy (OPCA) and the actions of environmental,exogenous neurotoxins.

U.S. Pat. No. 6,172,085 describes cyclic ether compounds as sodiumchannel blockers in a rat cerebral cortex fraction binding model andmethods for treating central nervous system (CNS) diseases and disorderssuch as CNS ischemia, CNS trauma (brain trauma, spinal cord injury orwhiplash injury), epilepsy, neurodegenerative diseases (ALS, Alzheimer'sdisease, Huntington's chorea, Parkinson's disease or diabeticneuropathy), vascular dementia (multi-infarct dementia or Binswanger'sdisease), manic-depressive psychosis, depression, schizophrenia, chronicpain, trigeminal neuralgia, migraine and cerebral edema.

U.S. Pat. No. 6,051,583 describes substituted2,3,3a,4,9,9a-hexahydro-8-hydroxy-1H-benz[f]indole derivatives as sodiumchannel blockers in a BTX-binding assay (S. W. Postma & W. A. Catterall,Mol. Pharmacol., 1984 25, 219-227) and in patch-clamp experiments (W. A.Catterall, Trends Pharmacol. Sci., 1987, 8, 57-65), as anticonvulsantsin a mouse MES model (M. A. Rogawski and R. J. Porter, Pharmacol. Rev.,1990, 42, 223-286), as neuroprotective agents in a veratridine inducedglutamate inhibition assay (S. Villauneva, P. Frenz, Y. Dragnic and F.Orrego, Brain Res., 1988, 461, 377-380) and in a rat-MCAO-model (U.Pschorn and A. J. Carter, J. Stroke Cerebrovascular Diseases, 1996, 6,93-99) and methods for treating neurodegenerative diseases (resultingfrom arrhythmia, spasm and cardiac and cerebral ischaemia,hypoglycaemia, hypoxia, anoxia, brain trauma, cerebral oedema, strokeand perinatal asphyxia) and those associated with epilepsy, amylotropiclateral sclerosis, Huntington's disease, Alzheimer's disease,Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, disordersof heart rhythm, angina pectoris, pain (nociceptor pain, neuropathicpain, pain resulting from damage to the peripheral or central nervoussystem (after amputation, paraplegia, herpes or in diabeticpolyneuropathy) and pain caused by functional disorders (migraine andback pain)).

PCT application WO 01/23570 describes voltage-gated sodium channel β1Asubunit splice variant nucleic acids and proteins as useful in thetreatment of neuropathic pain. PCT application WO 00/61231 describes theuse of sodium channel antagonists for treating diseases mediated orexacerbated by sensory neuronal apoptosis: in particular, pain states(such as chronic pain) following nerve insult associated with tissuedamage (due to injury or infection), neurodegenerative diseases (such asmultiple sclerosis and Parkinson's disease) and inflammation. PCTapplication WO 00/02865 describes the use of pharmaceutical agents inblocking the activity of voltage-sensitive sodium channels for treatingneuronal damage resulting from acute events such as ischemia or hypoxiaor from neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease, Huntington's disease, or lateral amyotrophicsclerosis.

SUMMARY OF THE INVENTION

The present invention provides aroyl pyrrole heteroaryl methanone andmethanol compounds as agents for treating or modulating a centralnervous system disorder selected from Formula (I) or Formula (II):

wherein

-   -   A is selected from the group consisting of aryl (optionally        substituted with 1 to 4 substituents independently selected from        the group consisting of halogen, C₁₋₈alkyl, C₁₋₈alkoxy, hydroxy,        hydroxy(C₁₋₈)alkyl, hydroxy(C₁₋₈)alkoxy, (halo)₁₋₃(C₁₋₈)alkyl        and (halo)₁₋₃(C₁₋₈)alkoxy) and    -   heteroaryl (optionally substituted on 1 to 4 available carbon        atom ring members with a substituent selected from the group        consisting of halogen, C₁₋₈alkyl, C₁₋₈alkoxy, hydroxy,        hydroxy(C₁₋₈)alkyl, hydroxy(C₁₋₈)alkoxy, (halo)₁₋₃(C₁₋₈)alkyl        and (halo)₁₋₃(C₁₋₈)alkoxy; and, optionally substituted on        available nitrogen atom ring members with a substituent selected        from the group consisting of C₁₋₈alkyl, hydroxy(C₁₋₈)alkyl and        (halo)₁₋₃(C₁₋₈)alkyl);    -   B is selected from heteroaryl optionally substituted on 1 to 4        available carbon atom ring members with a substituent selected        from the group consisting of halogen, C₁₋₈alkyl, C₁₋₈alkoxy,        hydroxy, hydroxy(C₁₋₈)alkyl, hydroxy(C₁₋₈)alkoxy,        (halo)₁₋₃(C₁₋₈)alkyl and (halo)₁₋₃(C₁₋₈)alkoxy; and, optionally        substituted on available nitrogen atom ring members with a        substituent selected from the group consisting of C₁₋₈alkyl,        C₂₋₈alkenyl, hydroxy(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkyl and oxido;    -   Z is selected from the group consisting of oxo and hydroxy;    -   R¹ is selected from the group consisting of:    -   C₁₋₈alkyl {wherein alkyl is optionally substituted on a terminal        carbon with one substituent selected from the group consisting        of C₁₋₈alkoxy, —C(O)— (substituted with one substituent selected        from the group consisting of H, OH, C₁₋₈alkyl, C₁₋₈alkoxy, NH₂,        —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂), —NHC(O)— (substituted with        one substituent selected from the group consisting of H, OH,        C₁₋₈alkyl, C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂),        —OC(O)— (substituted with one substituent selected from the        group consisting of H, OH, C₁₋₈alkyl, C₁₋₈alkoxy, NH₂,        —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂), NH₂, —NH(C₁₋₈)alkyl,        —N((C₁₋₈)alkyl)₂, —S(C₁₋₈)alkyl, —SO₂(C₁₋₈)alkyl, cyano,        (halo)₁₋₃, hydroxy and nitro},    -   cycloalkyl and aryl {wherein cycloalkyl and aryl are optionally        substituted with 1 to 4 substituents independently selected from        the group consisting of cyano, halo, hydroxy and nitro; and,        wherein cycloalkyl and aryl are optionally substituted with one        substituent selected from the group consisting of C₁₋₈alkyl,        (wherein alkyl is optionally substituted on a terminal carbon        with one substituent selected from the group consisting of NH₂,        —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂, cyano, (halo)₁₋₃, hydroxy and        nitro), C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl and —N((C₁₋₈)alkyl)₂};    -   R² and R³ are independently selected from the group consisting        of hydrogen, C₁₋₈alkyl and halogen;    -   and pharmaceutically acceptable acid addition salts, quaternary        ammonium salts and N-oxides thereof.

Embodiments of the present invention include a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound selected from Formula (I) or Formula (II) and a method for useof a compound selected from Formula (I) or Formula (II) for treating ormodulating a central nervous system disorder.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention include compounds selected fromFormula (I) or Formula (II) wherein A is selected from aryl optionallysubstituted with 1 to 4 substituents independently selected from thegroup consisting of halogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy,hydroxy(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkoxy, (halo)₁₋₃(C₁₋₄)alkyl and(halo)₁₋₃(C₁₋₄)alkoxy; wherein aryl is selected from an aromaticmonocyclic ring having six members or an aromatic bicyclic ring havingten members.

Preferably, A is selected from the group consisting of phenyl andnaphthalenyl optionally substituted with 1 to 4 substituents, aspreviously described.

More preferably, A is selected from phenyl optionally substituted with 1to 4 substituents, as previously described.

Preferably, the aryl substituents of A are independently selected fromthe group consisting of halogen, C₁₋₄alkyl and hydroxy.

More preferably, the aryl substituents of A are independently selectedfrom the group consisting of chlorine, fluorine, methyl and hydroxy.

Most preferably, the aryl substituents of A are independently selectedfrom the group consisting of chlorine, fluorine and methyl.

Embodiments of the present invention include compounds selected fromFormula (I) or Formula (II) wherein A is selected from heteroaryloptionally substituted on 1 to 4 available carbon atom ring members witha substituent selected from the group consisting of halogen, C₁₋₄alkyl,C₁₋₄alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkoxy,(halo)₁₋₃(C₁₋₄)alkyl and (halo)₁₋₃(C₁₋₄)alkoxy; and, optionallysubstituted on available nitrogen atom ring members with a substituentselected from the group consisting of C₁₋₄alkyl, hydroxy(C₁₋₄)alkyl and(halo)₁₋₃(C₁₋₄)alkyl; wherein heteroaryl is selected from an aromaticmonocyclic ring having five members of which at least one member is a N,O or S atom and which optionally contains one, two or three additional Natoms, an aromatic monocyclic ring having six members of which one, twoor three members are a N atom, an aromatic bicyclic ring having ninemembers of which at least one member is a N, O or S atom and whichoptionally contains one, two or three additional N atoms or an aromaticbicyclic ring having ten members of which one, two or three members area N atom.

Preferably, the heteroaryl of A is selected from the group consisting offuryl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl optionallysubstituted on 1 to 4 available carbon atom ring members with asubstituent, as previously described; and, optionally substituted onavailable nitrogen atom ring members with a substituent, as previouslydescribed.

More preferably, the heteroaryl of A is selected from the groupconsisting of thienyl, pyridinyl, quinolinyl and isoquinolinyloptionally substituted on 1 to 4 available carbon atom ring members witha substituent, as previously described; and, optionally substituted onavailable nitrogen atom ring members with a substituent, as previouslydescribed.

Most preferably, the heteroaryl of A is selected from the groupconsisting of thienyl and pyridinyl optionally substituted on 1 to 4available carbon atom ring members with a substituent, as previouslydescribed; and, optionally substituted on available nitrogen atom ringmembers with a substituent, as previously described.

Preferably, the heteroaryl substituents of A optionally substituted on 1to 4 available carbon atom ring members are independently selected fromthe group consisting of halogen and C₁₋₄alkyl; and, optionallysubstituted on available nitrogen atom ring members are selected fromC₁₋₄alkyl.

More preferably, the heteroaryl substituents of A optionally substitutedon 1 to 4 available carbon atom ring members are independently selectedfrom the group consisting of chlorine, fluorine and methyl; and,optionally substituted on available nitrogen atom ring members areselected from methyl.

Embodiments of the present invention include compounds selected fromFormula (I) or Formula (II) wherein B is heteroaryl optionallysubstituted on 1 to 4 available carbon atom ring members with asubstituent selected from the group consisting of halogen, C₁₋₄alkyl,C₁₋₄alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkoxy,(halo)₁₋₃(C₁₋₄)alkyl and (halo)₁₋₃(C₁₋₄)alkoxy; and, optionallysubstituted on available nitrogen atom ring members with a substituentselected from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl,hydroxy(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkyl and oxido; wherein heteroarylis selected from an aromatic monocyclic ring having five members ofwhich at least one member is a N, O or S atom and which optionallycontains one, two or three additional N atoms, an aromatic monocyclicring having six members of which one, two or three members are a N atom,an aromatic bicyclic ring having nine members of which at least onemember is a N, O or S atom and which optionally contains one, two orthree additional N atoms or an aromatic bicyclic ring having ten membersof which one, two or three members are a N atom.

Preferably, the heteroaryl of B is selected from the group consisting offuryl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyloptionally substituted on 1 to 4 available carbon atom ring members witha substituent, as previously described; and, optionally substituted onavailable nitrogen atom ring members with a substituent, as previouslydescribed.

More preferably, the heteroaryl of B is selected from the groupconsisting of furyl, thienyl, pyrrolyl, imidazolyl, pyridinyl,quinolinyl and isoquinolinyl optionally substituted on 1 to 4 availablecarbon atom ring members with a substituent, as previously described;and, optionally substituted on available nitrogen atom ring members witha substituent, as previously described.

Most preferably, the heteroaryl of B is selected from the groupconsisting of thienyl, imidazolyl and pyridinyl optionally substitutedon 1 to 4 available carbon atom ring members with a substituent, aspreviously described; and, optionally substituted on available nitrogenatom ring members with a substituent, as previously described.

Preferably, the substituents of B optionally substituted on 1 to 4available carbon atom ring members are independently selected from thegroup consisting of halogen and C₁₋₄alkyl; and, optionally substitutedon a nitrogen atom ring member are selected from oxido.

More preferably, the substituents of B optionally substituted on 1 to 4available carbon atom ring members are independently selected from thegroup consisting of chlorine and methyl; and, optionally substituted ona nitrogen atom ring member are selected from oxido.

Embodiments of the present invention include those compounds wherein, R¹is selected from the group consisting of:

-   -   C₁₋₄alkyl {wherein alkyl is optionally substituted on a terminal        carbon with one substituent selected from the group consisting        of C₁₋₄alkoxy, —C(O)— (substituted with one substituent selected        from the group consisting of H, OH, C₁₋₄alkyl, C₁₋₄alkoxy, NH₂,        —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂), —NHC(O)— (substituted with        one substituent selected from the group consisting of H, OH,        C₁₋₄alkyl, C₁₋₄alkoxy, NH₂, —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂),        —OC(O)— (substituted with one substituent selected from the        group consisting of H, OH, C₁₋₄alkyl, C₁₋₄alkoxy, NH₂,        —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂), NH₂, —NH(C₁₋₄)alkyl,        —N((C₁₋₄)alkyl)₂, —S(C₁₋₄)alkyl, —SO₂(C₁₋₄)alkyl, cyano,        (halo)₁₋₃, hydroxy and nitro},    -   cycloalkyl and aryl {wherein cycloalkyl and aryl are optionally        substituted with 1 to 4 substituents independently selected from        the group consisting of cyano, halo, hydroxy and nitro; and,        wherein cycloalkyl and aryl are optionally substituted with one        substituent selected from the group consisting of C₁₋₄alkyl,        (wherein alkyl is optionally substituted on a terminal carbon        with one substituent selected from the group consisting of NH₂,    -   —NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂, cyano, (halo)₁₋₃, hydroxy and        nitro), C₁₋₄alkoxy, NH₂, —NH(C₁₋₄)alkyl and —N((C₁₋₄)alkyl)₂}.

Preferably, R¹ is selected from C₁₋₄alkyl optionally substituted on aterminal carbon with a substituent, as previously described.

More preferably, R¹ is selected from C₁₋₄alkyl.

Preferably, the optional substituent on the terminal carbon of C₁₋₄alkylis selected from the group consisting of C₁₋₄alkoxy, NH₂,—NH(C₁₋₄)alkyl, —N((C₁₋₄)alkyl)₂, cyano, (halo)₁₋₃, hydroxy and nitro.

Embodiments of the present invention include those compounds wherein,preferably, R² and R³ are independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl and halogen. More preferably, R² andR³ are independently selected from the group consisting of hydrogen andC₁₋₄alkyl. Most preferably, R² and R³ are independently selected fromthe group consisting of hydrogen and methyl.

Exemplifying the invention is a compound selected from Formula (I):TABLE 1 Formula (I)

wherein A, B, Z, R² and R³ are dependently selected from Cpd A B Z R² R³1 4-Cl-Ph 4-pyridinyl O H H; 2 Ph 4-pyridinyl O H H; 3 4-Me-Ph4-pyridinyl O H H; 5 4-Cl-Ph 4-pyridinyl O H H; 6 4-Cl-Ph 2-pyridinyl OH H; 12 4-Cl-Ph 4-pyridinyl OH H H; 13 4-Cl-Ph 1H-imidazol-5-yl O H H;14 4-Cl-Ph 1-Me-4-pyridinyl O H H; 15 4-Cl-Ph 1-oxido-4-pyridinyl O H H;16 4-Cl-Ph 1-oxido-4-pyridinyl OH H H; 18 4-Cl-Ph 4-pyridinyl OH CH₃CH₃; and, 19 4-Cl-Ph 2-Cl-4-pyridinyl O H H;and pharmaceutically acceptable acid addition salts, quaternary ammoniumsalts and N-oxides thereof.

Emplifying the invention is a compound selected from Formula (II): TABLE2 Formula (II)

wherein B, A, R² and R³ are dependently selected from Cpd B A R² R³ 42-thienyl 4-pyridinyl H H; 7 3-pyridinyl 4-F-Ph H H; 8 3-pyridinyl2-naphthalenyl H H; 9 6-Cl-3-pyridinyl 4-Cl-Ph H H; 10 2-pyridinyl4-F-Ph H H; 11 4-pyridinyl 4-F-Ph H H; and, 17 3-pyridinyl 4-F-Ph CH₃CH₃;and pharmaceutically acceptable acid addition salts, quaternary ammoniumsalts and N-oxides thereof.

An embodiment of the present invention includes a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound selected from Formula (I) or Formula (II).

To prepare the pharmaceutical compositions of this invention, one ormore compounds selected from Formula (I) or Formula (II) are intimatelyadmixed with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration (e.g., oral, topical, suppository or parenteral).

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as suspensions, elixirs and solutions suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, coloring agents and the like. For solid oralpreparations such as powders, capsules and tablets or for topicalpreparations such as creams suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe sugar coated or enteric coated by standard techniques. Suppositoriesmay be prepared, in which case cocoa butter could be used as thecarrier. For parenterals, the carrier will usually comprise sterilewater, though other ingredients, for example, for purposes such asaiding solubility or for preservation, may be included. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed. For topicalagents, suitable diluents, granulating agents, lubricants anddisintegrating agents should be employed to aid dispersion andabsorbtion.

The pharmaceutical compositions herein may contain, per dosage unit(e.g., tablet, capsule, powder, injection, teaspoonful, suppository andthe like) from about 0.001 mg to about 500 mg of the active ingredient.

The terms used in describing the invention are commonly used and knownto those skilled in the art. As used herein, the following abbreviationshave the indicated meanings: DCE 1,2-dichloroethane Et₂O Diethyl etherEtOH Ethanol h Hour K₂CO₃ Potassium carbonate MeOH Methanol min MinuteMTBE Methyl-t-butyl ether 2-PrOH 2-Propanol

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

SCHEME A exemplifies the preparation of target compounds wherein A is atthe 2-position of the pyrrole and B is at the 4-position and Z is oxo.Alternatively, by varying the starting materials and using the sameconditions outlined in Scheme A, target compounds wherein B is at the2-position of the pyrrole and A is at the 4-position and Z is oxo may beprepared.

Referring to Scheme A, in the first step a simple pyrrole Compound A1 isacylated with an appropriately substituted aroyl chloride Compound A2(A-C(O)Cl) to produce an aroyl pyrrole Compound A3. This acylation maybe carried out by simply heating the aroyl chloride Compound A2 and thepyrrole Compound A1 in an aprotic solvent. The temperature of theacylation will vary depending upon the desired rate of reaction and thesubstituents of pyrrole Compound A1. Preferably, the acylation iscarried out at a temperature of from about 50° C. to about 250° C.

Subsequently, the aroyl pyrrole Compound A3 is acylated at the4-position in a Friedel-Crafts reaction with a heteroaryl methanonechloride compound (B—C(Z)Cl; where Z is oxo) Compound A4 to produce thedesired product Compound A5. The Friedel-Crafts reaction is preferablycarried out at a temperature of from about 0° C. to about 100° C.Suitable Friedel-Crafts Lewis acid catalysts include aluminum chloride,zinc chloride, BF₃ or TiCl₄. Suitable solvents include methylenechloride, 1,2-dichloroethane, carbon tetrachloride, nitromethane,nitrobenzenene, dichlorobenzene or chloroform.

An alternative route to the preparation of compounds wherein A is anaryl or heteroaryl group at the 2-position of the pyrrole and B is aheteroaryl group at the 4-position and Z is oxo is illustrated in SCHEMEB.

The 2-aroylpyrrole Compound A3 (wherein A is an aryl group and Z is oxo)is subjected to Freidel-Crafts formylation using 1,1-dichloromethylmethyl ether and a suitable Friedel-Crafts Lewis acid catalyst such asaluminum chloride, zinc chloride, BF₃ or TiCl₄ to give the2-aroyl-4-pyrrol-2 carboxaldehyde Compound B1. The Friedel-Craftsreaction is carried out at a temperature of from about −40° C. to about50° C. Suitable solvents include methylene chloride, 1,2-dichloroethane,carbon tetrachloride nitromethane, nitrobenzene, dichlorobenzene,chloroform or mixtures thereof. The aldehyde was then caused to reactwith the B-metal Compound B2 (wherein B is a heteroaryl group) to givethe carbinol Compound B3. Suitable heteroaryl-metal compounds includeorganolithium, organomagnesium (Grignard) and organozinc compounds. Suchheteroaryl-metal compounds may be prepared by metal halogen exchangebetween a halo heteroaromatic compound and a simple organometallic suchas n-butyllithium, ethyl magnesium bromide or diethyl zinc. Preferredsolvents for this for this two step procedure are ethereal solvents suchas diethyl ether or THF. The metal halogen-halogen exchange reaction maybe carried out at temperatures of from about −78° C. to about 25° C.Addition of the heteroaryl-metal compound to the aIdehyde can be carriedout at temperature of from about −78° C. to about 50° C.

The carbinol Compound B3 was then oxidized to the corresponding ketoneCompound B4 using a suitable oxidant (O) such as manganese dioxide,chromium trioxide or potassium permanganate. The manganese dioxideoxidation was carried out by stirring in a halocarbon or hydrocarbonsolvent. When the desired heterocyclic starting material bears an acidicor sensitive functionality, the overall sequence may be carried out witha protecting group such as trityl or benzyl on the heterocycle. Theprotecting group may then be removed after the organometallic additionby hydrogenolysis or acid treatment.

SCHEME C illustrates the formation of simple derivatives of the instantcompounds wherein A is an aryl group at the 2-position of the pyrroleand B is a heteroaryl group at the 4-position and Z is oxo.

When the 2-aroyl-4-heteroaroylpyrrole Compound C1 is treated with analkyl or alkenyl halide, the corresponding alkyl or alkenyl quaternaryammonium salt Compound C2 (wherein X is alkyl or alkenyl) is produced.The reaction may be carried out in an inert solvent such as ethylacetate, benzene, toluene, THF or ether. It may be carried out at fromabout 25° C. to the reflux temperature of the solvent.

When the 2-aroyl-4-heteroaroylpyrrole Compound C1 is treated with aperacid such as m-chloroperbenzoic acid or peracetic acid, thecorresponding oxido Compound C2 (wherein X is O) is produced. Thereaction may be carried out in an inert solvent such as methylenechloride or chloroform at temperatures of about 0° C. to about 50° C.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm.Sci., 1997 (January), 66, 1, 1). Other salts may, however, beuseful in the preparation of compounds according to this invention or oftheir pharmaceutically acceptable salts. Representative organic orinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.It is to be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Specific Synthetic Methods

Specific compounds which are representative of this invention may beprepared as per the following examples offered by way of illustrationand not by way of limitation. Also, examples specifically used toprepare intermediates for the further synthesis of compounds of theinvention are designated by “Procedure.” No attempt has been made tooptimize the yields obtained in any of the reactions. One skilled in theart would know how to increase such yields through routine variations inreaction times, temperatures, solvents and/or reagents.

EXAMPLE 1 [5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]pyridin-4-ylmethanone (Cpd 1)

A solution of 17.5 g (0.08 mole) of(4-chlorophenyl)(1-methyl-1H-pyrrol-2-yl)methanone, 14.4 g (0.088 mole)of isonicotinoyl chloride and 26.6 g of aluminum chloride (0.2 mole) in280 mL of DCE was heated under reflux for 16 h. After cooling, themixture was partitioned between CH₂Cl₂ and dilute NaOH solution. Theorganic layer was dried and the solvent was evaporated in vacuo. Theresidue was triturated with ether. The resulting solid wasrecrystallized from 2-PrOH to give 7 g (27%) of the title compound, mp174-175° C. ES-MS m/z=325 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 4.1 (s, 3H);7.1 (s, 1H); 7.3(dd, 2H); 7.42 (dd, 2H); 7.45 (s,1 H); 7.8 (dd, 2H); 8.8(dd, 2H). Anal calc'd for: C₁₈H₁₃ClN₂O₂: C, 66.57; H, 4.03; N, 8.63.Found: C, 66.34; H, 3.94; N, 8.53.

EXAMPLE 2 (5-Benzoyl-1-methyl-1H-pyrrol-3-yl) pyridin-4-ylmethanone (Cpd2)

Following the protocol of Example 1 and employing(1-methyl-1H-pyrrol-2-yl)-phenylmethanone in place of(4-chlorophenyl)(1-methyl-1H-pyrrrol-2-yl)methanone, the title compoundwas obtained in crude form and purified by flash chromatography (20%acetone in hexane): mp 127-129° C. ES-MS m/z=290 (M⁺+H). ¹H NMR (300MHz, DMSO-d₆) δ 4.05 (s, 3H); 7.0 (s, 1H); 7.6 (m, 5H); 7.8 (m, 4H);7.95 (s, 1H).

EXAMPLE 3[1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-3-yl]pyridin-4-ylmethanoneHydrochloride (Cpd 3)

Following the protocol of Example 1 and employing(1-methyl-1H-pyrrol-2-yl)-p-tolylmethanone in place of(4-chlorophenyl)(1-methyl-1H-pyrrrol-2-yl)methanone, the title compoundwas obtained in crude form, was treated with 3N HCl to give thehydrochloride salt and recrystallized from MeOH/EtOH: mp 134-136° C.ES-MS m/z=305 (M⁺+H). ¹H NMR (300 MHz, DMSO-d₆) δ 2.44 (s, 3H); 4.0 (s,3H); 7.03 (s, 1H); 7.4 (dd, 2H); 7.75 (dd, 2H); 8.0 (dd, 2H); 8.05(s,1H); 8.95 (dd, 2H). Anal calc'd for: C₁₉H₁₆N₂O₂.HCl: C, 66.96; H,5.03; N, 8.22. Found: C, 67.2; H, 4.99; N, 8.0.

EXAMPLE 4[1-Methyl-5-(thiophene-2-carbonyl)-1H-pyrrol-3-yl]pyridin-4-ylmethanoneHydrochloride (Cpd 4)

Following the protocol of Example 1 and employing(1-methyl-1H-pyrrol-2-yl)-thiophen-2-ylmethanone place of(4-chlorophenyl)(1-methyl-1H-pyrrrol-2-yl)methanone, the title compoundwas obtained in crude form, treated with 3N HCl to give thehydrochloride salt and purified by flash chromatography (10% MeOH inCH₂Cl₂): mp 243-245° C. ES-MS m/z=297 (M⁺+H). ¹H NMR (300 MHz, DMSO-d₆)δ 4.0 (s, 3H); 7.3 (t, 1H); 7.4 (s, 1H); 7.9 (m, 3H); 8.02 (s, 1H); 8.1(d, 1H); 8.95 (dd, 2H). Anal calc'd for: C₁₆H₁₂N₂O₂S.HCl: C, 57.74; H,3.94; N, 8.42. Found: C, 57.61; H, 3.99; N, 8.21.

EXAMPLE 5 [5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]

pyridin-3-ylmethanone Hydrochoride Hydrate [2:1:1] (Cpd 5) Following theprotocol of Example 1 and employing nicotinoyl chloride hydrochloride inplace of isonicotinoyl chloride hydrochloride, the title compound wasobtained in crude form and purified by flash chromatography (30% acetonein hexane). The hydrochloride salt was obtained from THF/Et₂O/HCl: mp138-140° C. ES-MS m/z=325 (M⁺+H). ¹H NMR (300 MHz, DMSO-d₆) δ 4.05 (s,3H); 5.0 (br s, 2H), 7.1 (s, 1H); 7.62 (dd, 2H); 7.72 (m, 1H); 7.82 (dd,2H); 8.1(s, 1H); 8.35 (m, 3H); 8.9 (m, 1H); 9.07 (s, 1H). Anal calc'dfor: C₁₈H₁₃ClN₂O₂. 0.5 HCl. 0.5 H₂O: C, 66.96; H, 5.03; N, 8.22. Found:C, 67.2; H, 4.99; N, 8.0.

EXAMPLE 6 [5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]pyridin-2-yl-methanone (Cpd 6)

Following the protocol of Example 1 and employing picolinoyl chloridehydrochloride in place of isonicotinoyl chloride hydrochloride, thetitle compound was obtained in 36% yield, recrystallized twice from2-PrOH and once from EtOAc: mp 138-139° C. ES-MS m/z=325 (M⁺+H). ¹H NMR(300 MHz, CDCl₃) δ 4.1 (s, 3H); 7.5 (dd, 2H); 7.55 (m, 2H); 7.84 (dd,2H); 7.9 (t,1H); 8.1(d, 1H); 8.35 (s, 1H); 8.7 (d, 1H). Anal calc'd for:C₁₈H₁₃ClN₂O₂: C, 66.57 H, 4.03; N, 8.63. Found: C, 67.2; H, 4.99; N,8.0. Found: C, 66.2; H, 4.11; N, 8.55.

Procedure 1 (1-Methyl-1H-pyrrol-2-yl)pyridin-3-ylmethanone

A mixture of 25 g (0.14 moles) of nicotinoyl chloride hydrochloride and10.4 mL (0.14 mole) of N-methylpyrrole was heated under reflux in 200 mLof dry toluene while a nitrogen stream was bubbled slowly through thereaction mixture. After refluxing overnight the reaction mixture wascooled and the solid filtered off. The solid was converted the free baseby partitioning between Et₂O/3N NaOH. The organics were washed withwater, brine and dried (K₂CO₃). The residue was chromatographed onsilica (90:10:1 CH₂Cl₂:MeOH:NH₄OH) to give 8.9 g of(2-pyridinyl)(1-methyl-1H-pyrrol-2-yl)-methanone (34%) as a gum. Cl-MSm/z=188 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 9.0 (ar, 1H); 8.7 (ar, 1H);8.1 (ar, 1H); 7.4 (ar, 1H); 6.7 (ar, 1H); 6.2 (ar, 1H), 4.0 (s, 3H).

EXAMPLE 7(4-Fluorophenyl)-[1-methyl-5-(pyridine-3-carbonyl)-1H-pyrrol-3-yl]methanoneHydrochloride (Cpd 7)

A solution of 3.33 g (0.015 mole) of(1-methyl-1H-pyrrol-2-yl)-pyridin-3-yl-methanone hydrochloride, 1.94 mL(0.0165 mole) of 4-fluorobenzoyl chloride and 5 g of aluminum chloride(0.037 mole) in 50 mL of DCE was stirred at 25° C. for 16 h. The mixturewas partitioned between CH₂Cl₂ and dilute NaOH solution. The organiclayer was dried and the solvent was evaporated in vacuo. The residue wasflash chromatographed with 35% acetone in hexane to give 2.14 (46%yield) of the free base. The hydrochloride salt of the title compoundwas obtained from Et₂O/HCl: mp 220-223° C. ES-MS m/z=309 (M⁺+H). ¹H NMR(300 MHz, DMSO-d₆) δ 4.0 (s, 3H); 6.2 (br s, 2H); 7.16 (s, 1H); 7.35 (t,2H); 7.85 (m, 1H); 7.95 (m, 2H); 8.1 (s, 1H); 8.4 (d, 1H), 8.95 (d, 1H);9.05 (s, 1H); 10.5 (br s, 1H). Anal calc'd for: C₁₈H₁₃FN₂O₂.HCl: C,62.71; H, 4.09; N, 8.13. Found: C, 63.08; H, 4.23; N, 8.11.

EXAMPLE 8[1-Methyl-5-(pyridine-3-carbonyl)-1H-pyrrol-3-yl]naphthalen-2-yl-methanone(Cpd 8)

Following the protocol of Example 7 and employing 2-naphthoyl chloridehydrochloride in place of 4-fluorobenzoyl chloride and heating at 55°C., the title compound was obtained and recrystallized from EtOAc: mp132-133° C. ES-MS m/z=341 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 4.1 (s, 3H);7.25 (s, 1H); 7.45 (m, 1H); 7.56 (m, 3H); 7.9 (m, 4H); 8.15(d, 1H); 8.35(s, 1H); 8.8 (d, 1H); 9.05 (s, 1H). Anal calc'd for: C₂₂H₁₆N₂O₂: C,77.63; H, 4.74; N, 8.23. Found: C, 77.14; H, 4.55; N, 8.02.

Procedure 2 (6-Chloropyridin-3-yl )-(1-methyl-1H-pyrrol-2-yl)methanone

Following the protocol for Example 1 and employing 5-chloronicotinoylchloride hydrochloride in place of nicotinoyl chloride hydrochloride thetitle compound was obtained. ES-MS m/z=221 (M⁺+H). ¹H NMR (300 MHz,CDCl₃) δ 4.1 (s, 3H); 6.2 (m,1H); 6.75 (m, 1H); 7.0 (s, 1H); 7.45(d,1H); 8.05 (d,1H); 8.8 (s, 1H).

EXAMPLE 9(4-Chlorophenyl)-[5-(6-chloropyridine-3-carbonyl)-1-methyl-1H-pyrrol-3-yl]methanone(Cpd 9)

Following the protocol of Example 8 and employing(6-chloropyridin-3-yl)-(1-methyl-1H-pyrrol-2-yl)methanone hydrochloridein place of (1-methyl-1H-pyrrol-2-yl)-pyridin-3-ylmethanonehydrochloride and 4-chlorobenzoyl chloride in place of 4-fluorobenzoylchloride, the title compound was obtained and recrystallized from MTBE:mp 150-152° C. ES-MS m/z=360 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 4.1 (s,3H); 7.2 (s, 1H); 7.5 (m, 3H); 7.56 (s, 1H); 7.8 (dd, 2H); 8.05 (d, 1H);8.8 (s, 1H). Anal calc'd for C₁₈H₁₂Cl₂N₂O₂: 60.19; H, 3.37; N, 7.8.Found: C, 59.9; H, 3.34; N, 7.71.

Procedure 3 (1-Methyl-1H-pyrrol-2-yl )-pyridin-3-yl-methanonehydrochloride

Following the protocol for Example 1 and employing picolinoyl chloridehydrochloride in place of nicotinoyl chloride hydrochloride the titlecompound was obtained in 38% yield. ES-MS m/z=187 (M⁺+H). ¹H NMR (300MHz, CDCl₃) δ 4.05 (s, 3H); 6.2 (m, 1H); 6.95 (m,1H); 7.32 (m,1H); 7.42(m, 1H); 7.86 (m, 1H); 7.95 (d,1H); 8.7 (d,1H).

EXAMPLE 10(4-Fluorophenyl)-[1-methyl-5-(pyridine-2-carbonyl)-1H-pyrrol-3-yl]methanone(Cpd 10)

Following the protocol of Example 7 and employing(1-methyl-1H-pyrrol-2-yl)-pyridin-2-yl-methanone hydrochloride in placeof (1-methyl-1H-pyrrol-2-yl)-pyridin-3-yl-methanone hydrochloride, thetitle compound was obtained in 56%yield. It was recrystallized from2-PrOH: mp 159-161° C. ES-MS m/z=309 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ4.1 (s, 3H); 7.2 (m, 2H); 7.5 (m, 2H); 7.9 (m, 4H); 8.05 (d, 1H); 8.7(d, 1H). Anal calc'd for C₁₈H₁₃FN₂O₂: C, 70.12; H, 4.25; N, 9.09. Found:C, 70.01; H, 4.15; N, 8.88.

Procedure 4 (1-Methyl-1H-pyrrol-2-yl)-pyridin-4-ylmethanonehydrochloride

Following the protocol for Example 1 and employing isonicotinoylchloride hydrochloride in place of nicotinoyl chloride hydrochloride thetitle compound was obtained. ES-MS m/z=187 (M⁺+H). ¹H NMR (300 MHz,CDCl₃) δ 4.05 (s, 3H); 6.2 (m, 1H); 6.7 (m, 1H); 7.0 (s, 1H); 7.6 ( dd,2H); 8.75 (dd, 2).

EXAMPLE 11 (4-Fluorophenyl)-[1-methyl-5-(pyridine-4-carbonyl)-1H-pyrrol-3-yl]methanone (Cpd 11)

Following the protocol of Example 7 and employing(1-methyl-1H-pyrrol-2-yl)-pyridin-4-yl-methanone hydrochloride in placeof (1-methyl-1H-pyrrol-2-yl)-pyridin-3-yl-methanone hydrochloride, thetitle compound was obtained recrystallized from EtOAc: mp 155-7° C.ES-MS m/z=309 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 4.1 (s, 3H); 7.2 (m,3H); 7.5 (s, 1H); 7.6 (dd, 2H); 7.8 (dd, 2H), 8.8 (dd, 2H).

Procedure 5 5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde

To a mixture of 5.05 g (23 mmol) of(4-chlorophenyl)(1-methyl-1H-pyrrrol-2-yl)methanone and 6.11 g (46 mmol)of AlCl₃ in 42 mL of 1,2-dichloroethane and 42 mL of nitromethane at−20° C. under argon was added 2.27 mL (25.3 mmol) of1,1-dichlorodimethyl ether. The mixture was stirred at −20° C. for onehour and at 25° C. for 16 h. It was poured into ice/HCl and extractedwith CH₂Cl₂. The organic phase was dried (MgSO₄) and concentrated. Theresidue was recrystallized from EtOAc to give 2.5 g (43%) of the titlecompound as a maroon solid: Cl-MS m/z=248 (M⁺+H). ¹H NMR (300 MHz,CDCl₃) δ 4.1 (s, 3H); 7.1 (s, 1H); 7.45 (dd, 2H); 7.5 (s, 1H); 7.8 (dd,2H); 9.8 (s, 1H).

EXAMPLE 12(4-Chlorophenyl)-[4-(hydroxypyridin-4-yl-methyl)-1-methyl-1H-pyrrol-2-yl]-methanone(Cpd 12)

A solution of 1.36 g (8.64 mmol) of 4-bromopyridine in 12 mL of etherwas cooled to −40° C. under argon and 5.4 mL (8.64 mmol) of 1.6 Mn-butyllithium in hexane was added dropwise. A solution of 1.07 g (4.3mmol) of 5-(4-chloro-benzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde(obtained from Procedure 5) in 15 mL of THF was added dropwise(exotherm). The reaction was stirred for 5 min and poured into water andextracted with CH₂Cl₂. The organic phase was dried (MgSO₄) andconcentrated. The residue was flash chromatographed (50%acetone/hexane).The trailing spot was concentrated and recrystallized from EtOAc to give0.74 g (52% yield) of the title compound as a white solid: mp 145-146°C. ES-MS m/z=327 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 2.55 (s, 1H); 4.0 (s,3H); 5.8 (s, 1H); 6.56 (s, 1H); 6.8 (s, 1H); 7.3 (dd, 2H); 7.4 (dd, 2H);7.75 (dd, 2H); 8.55 (dd, 2H). Anal calc'd for C₁₈H₁₅ClN₂O₂: 66.16; H,4.63; N, 8.57. Found: C, 65.8; H, 4.65; N, 8.63.

Procedure 6 (4-Chlorophenyl)-{4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-1-methyl-1H-pyrrol-2-yl}methanone

To 4.4 g (0.01 mole) 4-iodo-1-tritylimidazole in 80 mL of CH₂Cl₂ wasadded dropwise 3.3 mL of 3.0 M ethylmagnesium bromide in Et₂O. Afterstirring for 1 h, a solution of 1.0 g (0.004 mole) of5-(4-chlorobenzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde in 10 mL ofCH₂Cl₂ was added dropwise. The resulting reaction mixture was stirredfor 2.5 h after which it was poured into water. The solid was filteredoff through celite. The organics from the filtrate were separated off,washed with water, brine and dried (Na₂SO₄). The solvent was evaporatedin vacuo to give 3.1 g of(4-chlorophenyl)-{4-[hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl]-1-methyl-1H-pyrrol-2-yl}-methanone:Cl-MS m/z=559 (M⁺+H). ¹HNMR (CDCl₃) δ 7.7 (m, 5H) 7.4-7.0 (m, 16H); 6.5(m, 1H); 3.75 (s, 3H).

Procedure 7(4-Chlorophenyl)-[1-methyl-4-(1-trityl-1H-imidazole-4-carbonyl)-1H-pyrrol-2-yl]methanone

A solution 2.2 g of(4-chloro-phenyl)-{4-[hydroxy-(1-trityl-1H-imidazol4-yl)-methyl]-1-methyl-1H-pyrrol-2-yl}methanonein 50 mL of CH₂Cl₂ was stirred with 2.5 g of activated manganese dioxideovernight. The reaction was filtered and the filtrate was evaporated invacuo to give 2.0 g of(4-chlorophenyl)-[1-methyl-4-(1-trityl-1H-imidazole-4-carbonyl)-1H-pyrrol-2-yl]methanone.Cl-MS m/z=556 (M⁺+H).

EXAMPLE 13 (4-Chlorophenyl)-[4-(3H-imidazole-4-carbonyl)-1-methyl-1H-pyrrol-2-yl]methanone (Cpd13)

A 2.0 g sample of1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-2-(1-trityl-1H-imidazol-4-yl)ethanonewas stirred in 50 mL of MeOH and 35 mL of 2N HCl for 5 h. The solventwas evaporated in vacuo and the resulting residue was passed through aBiotage Flash 40 L (silica gel ; CH₂Cl₂:MeOH) to give 0.14 g of(4-chlorophenyl)-[4-(3H-imidazole-4-carbonyl)-1-methyl-1H-pyrrol-2-yl]methanone:mp. 198-200° C. Cl-MS m/z=314 (M⁺+H). ¹HNMR (CD₃CN) δ 8.4 (ar, 1H);7.9-7.8 (ar, 4H); 7.7 (ar, 1H); 7.6 (ar, 3H); 7.5 (ar,1H); 4.0 (s, 3H);2.0 (m, 2H).

EXAMPLE 144-[[5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]carbonyl]-1-methylpyridiniumTrifluoromethanesulfonate Hydrate [5:1] (Cpd 14)

A mixture of 0.64 g (2 mmol) of[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]pyridin-4-ylmethanone and0.22 mL (2 mmol) methyl triflate was stirred for 16 h in 20 mL ofCH₂Cl₂. The solvent was evaporated and the residue recrystallized fromEtOAc to give 0.76 g (77% yield) of the title compound as a white solid:mp 113-114° C. ES-MS m/z=339 (M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 4.0 (s,3H); 4.55 (s, 3H), 7.32 (dd, 2H); 7.8 (m, 3H); 8.2 (dd, 2H); 9.0 (dd,2H). Anal calc'd for: C₁₉H₁₆ClN₂O₂.CF₃O₃S. 0.2 H₂O: C,48.77; H, 3.35; N,5.68; KF,0.73. Found: C, 48.91; H, 3.5; N, 5.57; KF,1.03.

EXAMPLE 15(4-Chlorophenyl)-[1-methyl-4-(1-oxypyridine-4-carbonyl)-1H-pyrrol-2-yl]methanone(Cpd 15)

A solution of 324 mg (10 mmol) of[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]pyridin-4-ylmethanone and300 mg (>10 mmol) m-chloroperbenzoic acid in 5 mL CHCl₃ for 3 h. Thesolution was washed with dilute NaOH, dried (Na₂SO₄) and concentrated.The residue was recrystallized from EtOAc to give 260 mg (76% yield) ofthe title compound as a white solid: mp 207-208° C. ES-MS m/z=341(M⁺+H). ¹H NMR (300 MHz, CDCl₃) δ 4.1 (s, 3H); 7.1 (s, 1H); 7.5 (dd,2H); 7.53 (s, 1H); 7.7 (dd, 2H); 7.8 (dd, 2H); 8.23 (dd, 2H).

EXAMPLE 16(4-Chlorophenyl)-{4-[hydroxy-(1-oxy-pyridin-4-yl)methyl]-1-methyl-1H-pyrrol-2-yl}methanone(Cpd 16)

Following the protocol of Example 15 and employing(4-chlorophenyl)-[4-(hydroxypyridin-4-yl-methyl]-1-methyl-1H-pyrrol-2-yllmethanonein place of [5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]pyridin-4-ylmethanone, the title compound wasobtained, recrystallized from CHCl₃ to give the title compound in 50%yield. ES-MS m/z=344 (M⁺+H). ¹H NMR (300 MHz, DMSO-d₆) δ 3.95 (s, 3H);5.58 (d, 1H); 5.9 (d, 1H); 6.6 (s, 1H); 7.15 (s, 1H); 7.4 (dd, 2H); 7.56(dd, 2H); 7.7 (dd, 2H); 8.1 (dd, 2H).

Procedure 8 Pyrid in-3-yl-(1,3,5-trimethyl-1H-pyrrol-2-yl )methanone

Following the protocol for Example 1 and employing1,2,4-trimethylpyrrole in place of N-methylpyrrole, the title compoundwas obtained: mp 195-197° C. Cl-MS m/z=215 (M⁺+H). ¹HNMR (CDCl₃) δ8.95:8.85 (ar, 2H); 8.7 (ar, 1H); 8.1 (ar, 1H); 5.9 (ar, IH); 3.8 (s,3H); 2.3 (s, 3H); 1.7 (s, 3H).

EXAMPLE 17(4-Fluorophenyl)-[1,2,4-trimethyl-5-(pyridine-3-carbonyl)-1H-pyrrol-3-yl]methanone(Cpd 17)

Following the protocol of Example 7 and employingpyridin-3-yl-(1,3,5-trimethyl-1H-pyrrol-2-yl)methanone hydrochloride inplace of (1-methyl-1H-pyrrol-2-yl)-pyridin-3-yl-methanone hydrochloride,the title compound was obtained. Mp 85-88° C. Cl-MS mlz=337 (M⁺+H).¹HNMR (DMSO-d₆) δ 8.85-8.75 (ar, 2H); 8.3 (ar, 1H); 7.8 (ar, 3H); 7.35(ar, 2H); 3.7 (s, 3H); 2.2 (s, 3H); 1.6 (s, 3H).

Procedure 9(4-Chlorophenyl)-[4-(hydroxypyridin-4-yl-methyl)-1,3,5-trimethyl-1H-pyrrol-2-yl]-methanone

By the method of Example 12 using5-(4-chlorobenzoyl)-1,2,4-trimethyl-1H-pyrrole-3-carbaldehyde in placeof 2-(4-chlorobenzoyl)-1-methyl-1H-pyrrole-3-carboxaldehyde gave thetitle compound in 47% yield. ES-MS m/z=355 (M⁺+H).

EXAMPLE 18(4-Chlorophenyl)-[4-(hydroxypyridin-4-yl-methyl)-1,3,5-trimethyl-1H-pyrrol-2-yl]methanone(Cpd 18)

By the method of Procedure 7 substituting(4-chlorophenyl)-[4-(hydroxypyridin-4-yl-methyl)-1,3,5-trimethyl-1H-pyrrol-2-yl]-methanonefor5-[[2-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-4-yl]carbonyl]-3-(triphenylmethyl)-1H-imidazolium the title compound was prepared. Treatment withethereal HCl gave 35% yield of the hydrochloride salt. Mp. 174-176° C.ES-MS m/z=353 (M⁺+H). ¹HNMR (CDCl₃) δ 8.9 (ar, 2H); 8 (ar, 2H); 7.7 (ar,2H); 7.5 (ar, 2H); 3.75 (s, 3H); 2.3 (s, 3H); 2.65 (s, 3H).

EXAMPLE 19(4-Chlorophenyl)-[4-(2-chloropyridine-4-carbonyl)-1-methyl-1H-pyrrol-2-yl]methanone(Cpd 19)

A solution of 3.6 g (0.010 mole) of4-[2-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-4-yl]-1-oxido-4-pyridinylmethanolin 32 mL of POCl₃ was refluxed for 4 h. After cooling the solvent wasevaporated in vacuo. The residue was taken up in CH₂Cl₂, washed with 3NNaOH, water, brine and dried (Na₂SO₄). The residue was taken up in 15 mLof EtOH and 15 mL of toluene and the water from the azeotropic mixturewas refluxed off with a Dean-Stark trap for 2 h. The solvent wasevaporated in vacuo. The residue was suspended in hot EtOH and the solidfiltered. The solid was dissolved in MeOH with 10% CH₂Cl₂ and etherealHCl was added. The solid was filtered to give a 24% yield of the titlecompound. Mp. 182-184° C. ES-MS m/z=359. ¹HNMR (DMSO-d₆) δ8.6 (ar, 1H);8.1 (ar, 1H); 7.9-7.7 (ar, 6H); 7.1 (ar, 1H); 4.0 (s, 3H).

BIOLOGICAL EXAMPLES

The compounds of the present invention are useful as agents for treatingor modulating a central nervous system disorder. The followingbiological examples demonstrate the use of the instant compounds fortreating or modulating a central nervous system disorder.

The methods of the present invention include a method for treating ormodulating a central nervous system disorder wherein the central nervoussystem disorder includes, and is not limited to, neuropathic pain,chronic pain (including chronic pain caused by inflammation or aninflammatory-related condition, osteoarthritis or rheumatoid arthritis),pain, neurological conditions (including epilepsy and bipolar disorder),cardiovascular diseases and other disorders (including functional boweldisorders), psychotic disorders, movement disorders, anxiety disordersor neurodegenerative disorders.

Neuropathic pain includes, and is not limited to, neuropathic painresulting from chronic or debilitating conditions (such as painfuldiabetic peripheral neuropathy, post-herpetic neuralgia, trigeminalneuralgia, post-stroke pain, multiple sclerosis-associated pain,neuropathies-associated pain (such as in idiopathic or post-traumaticneuropathy and mononeuritis), HIV-associated neuropathic pain,cancer-associated neuropathic pain, carpal tunnel-associated neuropathicpain, spinal cord injury-associated pain, complex regional painsyndrome, fibromyalgia-associated neuropathic pain, lumbar and cervicalpain, reflex sympathic dystrophy, phantom limb syndrome and otherchronic and debilitating condition-associated pain syndromes),sympathetically maintained pain or cluster and migraineheadache-associated pain; pain associated with cancer, fibromyalgia,back disorders or migraine and chronic headache, adiposis dolorosa andburn pain, central pain conditions following stroke, thalamic lesions ormultiple sclerosis or pain resulting from damage to the peripheral orcentral nervous system (after amputation, paraplegia, herpes or as aresult of diabetic polyneuropathy).

Chronic pain includes, and is not limited to, chronic pain caused byinflammation or an inflammatory-related condition, osteoarthritis,rheumatoid arthritis or as sequela to disease, acute injury or traumaand includes upper back pain or lower back pain (resulting fromsystematic, regional or primary spine disease (such as radiculopathy),inflammation or an inflammatory-related condition), bone pain (due toosteoarthritis, osteoporosis, bone metastases or unknown reasons),pelvic pain, spinal cord injury-associated pain, cardiac chest pain,non-cardiac chest pain, central post-stroke pain, myofascial pain,cancer pain, AIDS pain, sickle cell pain, geriatric pain or pain causedby headache (such as chronic or migraine), trigeminal neuralgia,temporomandibular joint syndrome, fibromyalgia syndrome, osteoarthritis,rheumatoid arthritis, gout, fibrositis or thoracic outlet syndromes andincludes use of the instant compounds as a local anesthetic for thetreatment thereof.

Pain includes, and is not limited to, pain that is centrally mediated,pain that is peripherally mediated, pain that is caused by structuraltissue injury, pain that is caused by soft tissue injury or pain that iscaused by progressive disease, acute pain (caused by acute injury,trauma, illness, sports-medicine injuries, carpal tunnel syndrome,burns, musculoskeletal sprains and strains, musculotendinous strain,cervicobrachial pain syndromes, dyspepsia, gastric ulcer, duodenalulcer, dysmenorrhea, endometriosis or surgery (such as open-heart orbypass surgery)), post-operative pain, kidney stone pain, gallbladderpain, gallstone pain, obstetric pain, rheumatological pain or dentalpain and includes use of the instant compounds as a local anesthetic forthe treatment thereof.

Neurological conditions include, and are not limited to, conditions suchas anxiety, convulsions, cyclophrenia, hypotonia, epilepsy (includingsimple partial seizures, complex partial seizures, secondary generalisedseizures and generalized seizures (further including absence seizures,myoclonic seizures, clonic seizures, tonic seizures, tonic clonicseizures and atonic seizures), bipolar disorder (such as bipolardisorder type I, bipolar disorder type II, cyclothymic disorder, rapidcycling, ultradian cycling, bipolar depression, acute mania, mania,mixed mania, hypomania and episodes associated with bipolar disorder) orunipolar depression.

Cardiovascular diseases and other disorders include, and are not limitedto, arrhythmias (including cardiac arrhythmia, cardiac infarction orangina pectoris), hypertension, endocrine disorders (such as acromegalyor diabetes insipidus), tinnitus, muscle spasm, urinary incontinence,diarrhea, pruritus, functional bowel disorders (such as non-ulcerdyspepsia, non-cardiac chest pain or irritable bowel syndrome), muscularsclerosis, macular degeneration or glaucoma, diseases in which thepathophysiology of the disorder involves excessive or hypersecretory orotherwise inappropriate cellular secretion of an endogenous substance(such as a catecholamine, a hormone or a growth factor) or emesis.

Psychotic disorders include, and are not limited to, schizophrenia(including paranoid schizophrenia, hebephrenic schizophrenia, catatonicschizophrenia, undifferentiated schizophrenia, post-schizophrenicdepression, residual schizophrenia, simple schizophrenia or unspecifiedschizophrenia), schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder or a psychotic disorder nototherwise specified.

Movement disorders include, and are not limited to, benign essentialtremor, tremor in Parkinson's disease, Parkinsonism tremor, othernon-related essential or Parkinsonism tremors (such as central tremorsor non-classic tremors (including head/limb resting tremor, simplekinetic tremor, intention tremor, orthostatic tremor, enhancedphysiologic tremor, psychogenic tremor, cerebellar tremor, rubral tremoror tremors associated with posture, position, voice or task) ordrug-induced tremors and movement disorders (such as postural tremor,acute dystonia, chorea, akathisia, tardive dyskinesia orParkinson's-like syndromes)), restless leg syndrome, restless armsyndrome, chorea in Huntington's disease, tremors associated withmultiple sclerosis or Gilles de La Tourette's syndrome, post-spinal cordinjury spasms, post-anoxic spasms, idiopathic torsion dystonia, focaltorsion dystonia, myoclonus, athetosis, paroxysmal movement disorders(such as paroxystic dystony, paroxystic ataxia or paroxystic tremors) orabnormal movements (such as Wilson's disease).

Anxiety disorders include, and are not limited to, generalized anxietydisorder, panic disorders (such as agoraphobia, panic disorders withoutagoraphobia, anticipatory anxiety, recurrent sleep panic attacks,distressing symptoms (such as dyspnea, tachycardia, palpitations,headaches, dizziness, paresthesias, choking, smothering feeling, nauseaor bloating) or feelings of impending doom); impulse control disorders(such as obsessive-compulsive disorder, bulimia, episodic dyscontrol,trichotillomania, compulsive gambling and kleptomania); phobic disorders(such as from social phobia, global social phobia, specific socialphobia, simple phobia, agoraphobia, apiphobia, tropophobia,astrapophobia, triskaidekaphobia, blennophobia, thalassophobia,claustrophobia, spheksophobia, cynophobia, sciophobia, decidophobia,eletrophobia, scholionophobia, eremophobia, pyrophobia, gamophobia,pnigerophobia, ophidiophobia, odynophobia, nyctophobia, ochlophobia,musophobia, keraunophobia, katagelophobia, kakorraphiophobia,hydrophobia, gynophobia, gatophobia, gephyrophobia, acrophobia oramathophobia); posttraumatic stress disorder, dissociative states (suchas amnesia, somnambulism, dissociative identity disorder ordepersonalization), presurgical anxiety states, postsurgical anxietystates or other medical or psychiatric induced anxiety conditions (suchas anxiety resulting from traumatic brain injury, chronic pain disordersor other chronic disease conditions.

Neurodegenerative disorders include, and are not limited to, acuteneurodegenerative disorders (such as those associated with an abruptinsult resulting from acute injury (such as brain trauma, focal braintrauma, diffuse brain damage, spinal cord injury, intracranial lesions(including contusion, penetration, shear, compression or lacerationlesions), intravertebral lesions (including contusion, penetration,shear, compression or laceration lesions) or whiplash shaken infantsyndrome) , anoxic ischemia, hypoxic ischemia, hypoglycemic ischemia(where the ischemia is a result of cerebrovascular insufficiency,cerebral ischemia or infarction (originating from edema, embolicocclusion, thrombotic occlusion, reperfusion following acute ischemia,perinatal hypoxic-ischemic or asphyxia injury, cardiac arrhythmia,ischemia, spasm or arrest or intracranial hemorrhage (such as epidural,subdural, subarachnoid or intracerebral hemorrhage)), drowning or carbonmonoxide poisoning) or the combination thereof resulting in neuronalcell death or compromise); chronic neurodegenerative disorders (such asthose associated with progressive neuronal cell death or compromise overa period of time (including Alzheimer's disease, Pick's disease, diffuseLewy body disease, progressive supranuclear palsy (such asSteel-Richardson syndrome), multisystem degeneration (such as Shy-Dragersyndrome), chronic epileptic conditions associated withneurodegeneration, motor neuron diseases (such as amyotrophic lateralsclerosis (ALS)), multiple sclerosis, degenerative ataxias, corticalbasal degeneration, ALS-Parkinson's-Dementia complex of Guam,HIV-induced dementia and blindness, subacute sclerosing panencephalitis,Huntington's disease, Parkinson's disease, Down's Syndrome, Korsakoff'sdisease, synucleinopathies (such as multiple system atrophy), primaryprogressive aphasia, striatonigral degeneration, Machado-Josephdisease/spinocerebellar ataxia type 3 and olivopontocerebellar atrophyor degeneration, Gilles De La Tourette's disease, bulbar andpseudobulbar palsy, spinal and spinobulbar muscular atrophy (such asKennedy's disease), primary lateral sclerosis, familial spasticparaplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease,Tay-Sach's disease, Sandhoff disease, familial spastic disease,Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressivemultifocal leukoencephalopathy, familial dysautonomia (such as Riley-Daysyndrome) or prion diseases (such as Creutzfeldt-Jakob disease,Gerstmann-Strätussler-Scheinker disease, Kuru disease or fatal familialinsomnia)); other acute or chronic neurodegenerative disordersassociated with memory loss (as a result of age-related dementia,vascular dementia, multi-infarct dementia, diffuse white matter disease(such as Binswanger's disease), dementia of endocrine or metabolicorigin, dementia of head trauma or diffuse brain damage, dementiapugilistica or frontal lobe dementia); or, other acute or chronicneurodegenerative disorders associated with neuronal injury (such asthose associated with chemical, toxic, infectious and radiation injuryof the nervous system, injury during fetal development, prematurity attime of birth, anoxic-ischemia, injury from hepatic, glycemic, uremic,electrolyte and endocrine origin, injury of psychiatric origin (as aresult of psychopathology, depression or anxiety), injury fromperipheral diseases and plexopathy (such as plexus palsies); and, injuryfrom neuropathy (as a result of multifocal, sensory, motor,sensory-motor, autonomic, sensory-autonomic or demyelinatingneuropathies (such as Guillain-Barre syndrome or chronic inflammatorydemyelinating polyradiculoneuropathy), from neuropathies originatingfrom infections, inflammation, immune disorders,dependence/tolerance/reverse tolerance to a dependence-inducing agent(such as alcohol, opioids, CNS depressants, psychostimulants ornicotine), pharmacological treatments, toxins, trauma (such ascompression, crush, laceration or segmentation traumas), metabolicdisorders (such as endocrine or paraneoplastic), Charcot-Marie-Toothdisease (such as type 1a, 1b, 2, 4a or 1-X linked), Friedreich's ataxia,metachromatic leukodystrophy, Refsum's disease, adrenomyeloneuropathy,Ataxia-telangiectasia, Déjerine-Sottas (type A or B), Lambert-Eatonsyndrome or disorders of the cranial nerves), from peripheralneuropathies (such as trigeminal neuralgia, postherpetic neuralgia,diabetic neuropathy, glossopharyngeal neuralgia, lumbar and cervicalradiculopathies, reflex sympathetic dystrophy and causalgia) or fromneuropathy secondary to metastatic infiltration); neuronal loss(associated with stroke, global and focal ischemia, CNS trauma,hypoglycemia, surgery and spinal cord trauma) and includes use of theinstant compounds as neuroprotective agents (treating neurodegenerationfollowing stroke, cardiac arrest, pulmonary bypass, traumatic braininjury and spinal cord injury.

BIOLOGICAL EXAMPLE 1

Screening Assay for Voltage-Gated Sodium Channel AntagonistsFluorometric Membrane Potential Assay

The activity of the present compounds as sodium channel modulatingagents was demonstrated by the fluorometric membrane potential assay inSK-N-SH cells as described below.

Procedure

SK-N-SH neuroblastoma cells were maintained in a propagation mediumcontaining modified Eagle's medium and 10% (v/v) fetal bovine serum andwere incubated at 37° C. in a 5% CO₂ atmosphere. Only cells with fewerthan 20 passages were used in each assay. All drugs were prepared inDMSO, and the final concentration of solvent was less than 0.1% (v/v).Veratridine, a toxin that selectively promotes persistent activation ofvoltage-gated sodium channels, served as the stimulus. 24 hr prior totesting, 1×10⁵ cells/well were plated into 96-well plates specificallydesigned for use in a fluorescent imaging plate reader (FLIPR)(Molecular Devices, Sunnyvale, Calif.).

Prior to screening, monolayers of cells were loaded with 100 μL/well ofa proprietary voltage-sensitive dye (Molecular Devices, Sunnyvale,Calif.) for 30 min at 37° C. After this incubation period, the cellswere stimulated with 5 μM veratridine in the presence or absence ofinvestigational compounds (prepared at a final concentration of 10 μM inDMSO). A sample containing 5 μM veratridine and 10 μM tetrodotoxinaccounted for nonspecific activity. The fluorescence was monitored bythe FLI PR (Molecular Devices) from 10 sec prior to drug addition (50μL) to 170 sec after drug addition at 25° C. During sodium channelactivation, the cells depolarize and the dye associates with cellmembranes, resulting in increased fluorescence.

Analysis

As shown in Table 3, the % fluorescence inhibition (% Fl) in themembrane by a calculated according to the formula:% Fl=100×[1−[(TCF−NSF)/(CCF−NSF)]];

wherein FTC if defined as Test Compound Fluorescence, CCF is ControlCompound Flourescence (where 5 μM veratridine was used as the control)and NSF is Non-Specific Flourescence. TABLE 3 Cpd % Fl at 10 μM 1 32 276 3 45 4 49 5 26 6 25 7 45 8 67 9 26 10 60 11 39 12 60 13 62 14 54 1540 16 29 17 15

The results of the flouorometric membrane potential assay suggest thatcompounds of the present invention may be effective in treating ormodulating a centeral nrevous system disorder.

For treating or modulating a central nervous system disorder, a compoundselected from Formula (I) or Formula (II) may be employed at a dailydosage in the range of from about 30 to about 4000 mg, usually in 2 to 4divided doses, for an average adult human. A unit dose would containfrom about 10 to about 500 mg of the active ingredient. More generally,for mammals, the treatment would comprise the daily administration offrom about 0.001 mg/kg to about 500 mg/kg.

In particular, a pharmaceutical composition of the present inventioncomprising a pharmaceutically acceptable carrier and a compound selectedfrom Formula (I) or Formula (II) administered orally may be especiallysuitable for use in treating or modulating a central nervous systemdisorder.

The present invention includes a method for treating or modulating acentral nervous system disorder comprising internally administering to asubject in need thereof a therapeutically effective amount of a compoundselected from Formula (I) or Formula (II) or a pharmaceuticalcomposition thereof.

BIOLOGICAL EXAMPLE 2

Screening Assay for Voltage-Gated Sodium Channel Antagonists [¹⁴ C]Guanidinium Flux Assay

The activity of the present compounds as sodium channel modulatingagents was demonstrated by the [¹⁴C]guanidinium flux assay in SK-N-SHcells as described below.

Procedure

SK-N-SH neuroblastoma cells were maintained in a propagation mediumcontaining modified Eagle's medium and 10% (v/v) fetal bovine serum andwere incubated at 37° C. in a 5% CO₂ atmosphere. Only cells with fewerthan 20 passages were used in each assay. All drugs were prepared inDMSO, and the final concentration of solvent was less than 0.1% (v/v).Veratridine, a toxin that selectively promotes persistent activation ofvoltage-gated sodium channels, served as the stimulus.

SK-N-SH cells were plated at 1×10⁵ cells/well in 96-well Cytostar-Tmicroscintillating plates in propagation medium and experiments wereperformed 6-7 days after plating. Prior to assay, the SK-N-SH cells werewashed twice with assay buffer containing 50 mM HEPES (pH 7.45), 5.4 mMpotassium chloride, 0.8 mM magnesium chloride, 130 mM choline chloride,5.5 mM glucose and 0.1 mg/mL bovine serum albumin. Next, the plates wereallowed to equilibrate for 10 min at 37° C. in assay buffer. After thisincubation period, the cells were stimulated with 100 μM veratridine inthe presence or absence of investigational compounds prepared in a96-well plate (prepared at a final concentration of 10 μM in DMSO). The96-well dosing plate was prepared by mixing 25 μL of a drug/assay buffersolution per well with 25 μL of 0.7 μCi/mL [¹⁴C]guanidine hydrochloridein assay buffer. 50 μL aliquots from the dosing plate were then added tothe cells. One sample containing 100 μM veratridine and 10 μMtetrodotoxin accounted for nonspecific activity. The plates wereincubated for 1 hr at room temperature and the radioactivity was countedin a 1450 Microbeta scintillation counter.

Analysis

As shown in Table 4, the % guanidinium flux inhibition (% GFI) by acompound tested was calculated according to the formula:% GFI=100×[1−[(TCC−NSC)/(CCC−NSC)]];

wherein TCC is defined as Test Compound Counts (per minute), CCC isControl Compound Counts (per minute; 100 μM veratridine was used as thecontrol) and NSC is Non-Specific Counts (per minute). TABLE 4 Cpd % GFlat 10 μM 1 23 5 55 6 74 7 57 8 82 9 31 10 46 12 4 @ 100 μM 13 24 14 1415  4

The results of the guanidinium flux assay suggest that compounds of thepresent invention may be effective in treating or modulating a centralnervous system disorder.

For treating or modulating a central nervous system disorder, a compoundselected from Formula (I) or Formula (II) may be employed at a dailydosage in the range of from about 30 to about 4000 mg, usually in 2 to 4divided doses, for an average adult human. A unit dose would containfrom about 10 to about 500 mg of the active ingredient. More generally,for mammals, the treatment would comprise the daily administration offrom about 0.001 mg/kg to about 500 mg/kg.

In particular, a pharmaceutical composition of the present inventioncomprising a pharmaceutically acceptable carrier and a compound selectedfrom Formula (I) or Formula (II) administered orally may be especiallysuitable for use in treating or modulating a central nervous systemdisorder.

The present invention includes a method for treating or modulating acentral nervous system disorder comprising internally administering to asubject in need thereof a therapeutically effective amount of a compoundselected from Formula (I) or Formula (II) or a pharmaceuticalcomposition thereof.

BIOLOGICAL EXAMPLE 3

Procedure for Testing in Mouse Anticonvulsant Model

The activity of the present compounds as anticonvulsant agents wasdetermined using a standard mouse “maximal electroshock test” (MES). Inthis test, activity was indicated by a block of the toxic extensorseizure, as described by Swinyard, et al. (J. Pharmacol. Exptl. Therap.,1952, 106, 319). A more recent description of current anticonvulsantdrug screening is given in Swinyard, et al., in Epilepsia, 1978,19, 409.

The anticonvulsant activity of the instant compounds is shown in Table 5and was evaluated according to the Swinyard (1952) method. Theabbreviations used in the table have the following meanings: mpk refersto the dose orally administered in “mg per Kg;” and, ED₅₀ refers to the“50% Effective Dose” orally administered in mpk. The values marked byan * represent the number of mice protected/number of mice tested;therefore, a value of 3/3 represents that the number of mice protectedmatched the number of mice tested at the indicated dose. TABLE 5 Cpd MESResponse 1 ED₅₀ = 156.97 mpk 3 3/3* @ 100 mpk 4 0/1* @ 300 mpk 6 1/1* @30 mpk 7 2/3* @ 100 mpk 8 0/1* @ 300 mpk 10 0/1* @ 300 mpk 11 0/1* @ 300mpk

The results of the mouse MES model suggest that compounds of the presentinvention may be effective in treating epilepsy or in modulating thesymptoms thereof.

For treating epilepsy or modulating the symptoms thereof, a compoundselected from Formula (I) or Formula (II) should not have A selectedfrom 2-naphthalenylcarbonyl attached to the pyrrole ring on the 4position or, independently, should not have B selected from2-thienylcarbonyl, 2-pyridinylcarbonyl or 4-pyridinylcarbonyl attachedto the pyrrole ring on the 2 position.

For treating epilepsy or modulating the symptoms thereof, a compoundselected from Formula (I) or Formula (II) may be employed at a dailydosage in the range of from about 30 to about 4000 mg, usually in 2 to 4divided doses, for an average adult human. A unit dose would containfrom about 10 to about 500 mg of the active ingredient. More generally,for mammals, the treatment would comprise the daily administration offrom about 0.001 mg/kg to about 50 mg/kg.

A compound selected from Formula (I) or Formula (II) may be used intreating epilepsy or in modulating the symptoms thereof in a mannersimilar to that used for phenytoin. Medical aspects of the treatment ofepilepsy are described in L. S. Goodman, et. al., in “ThePharmacological Basis of Therapeutics” , 5th Ed. pages 201 to 226,Macmillan (1975).

In particular, a pharmaceutical composition of the present inventioncomprising a pharmaceutically acceptable carrier and a compound selectedfrom Formula (I) or Formula (II) administered orally may be especiallysuitable for use in treating epilepsy or in modulating the symptomsthereof.

The present invention includes a method for treating epilepsy ormodulating the symptoms thereof comprising internally administering to asubject suffering from the symptoms of epilepsy a therapeuticallyeffective amount of a compound selected from Formula (I) or Formula (II)or a pharmaceutical composition thereof.

BIOLOGICAL EXAMPLE 4

Procedure for Testing Antiallodynic Effect

The procedure used to detect the antiallodynic effect of a compound ofthe present invention for which there is a good correlation with humanefficacy for the treatment of pain is the procedure for the measurementof allodynia found in the Chung Model (Kim S. H. and Chung J. M., AnExperimental Model for Peripheral Neuropathy Produced by SegmentalSpinal Nerve Ligation in the Rat, Pain, 1992, 50, 355-363). Theantiallodynic effect of the composition of the present invention in theChung Model is expressed in % MPE (Maximum Possible Effect).

Male Sprague-Dawley rats, weighing approximately 200 g each wereanesthetized with isoflurane. The spinal nerve at the level of L₅ wasexposed through an incision just left of the dorsal midline and tightlyligated with 6-0 silk. At various times after surgery, animals weretested for mechanical allodynia with von Frey hairs (monofilaments whichare calibrated to bend under a certain amount of pressure, ranging from0.41 to 15.1 g). In order to calculate a paw withdrawal threshold (PWT),tactile allodynia was measured by recording the pressure at which theaffected paw was withdrawn from graded stimuli according to theprocedure of S. R. Chaplan, J. W. Pogrel, T. L. Yaksh, Role ofVoltage-Dependent Calcium Channel Subtypes in Experimental TactileAllodynia, J. Pharmacol. Exp. Ther., 1994, 269, 1117-1123. Normal ratscan withstand at least 15 g of pressure without responding. Operatedrats, however, can respond to as little as 0.25 g of pressure. Thesurgery was deemed successful if the animal responded with a PWT of lessthan 4 g of pressure applied to the affected paw. Rats were included inthe study only if they did not exhibit motor dysfunction (e.g., pawdragging or dropping) and their PWT was below 39.2 mN (equivalent to 4.0g). The PWT was used to calculate the % maximal possible effect (% MPE)according to the formula:% MPE=100×[(PWT−CT)/(CO−CT)];wherein PWT is defined as Paw Withdrawal Threshold, CT is ControlThreshold, and CO is Cut Off (defined as 15 g).

The sham operation consisted of a similar surgery; the spinal nerve wasvisualized without being ligated. These animals were also tested formechanical allodynia and showed no response to greater than 15 g offorce applied to the ipsilateral paw.

Compounds selected from Formula (I) and Formula (II) were tested foractivity in treating or modulating neuropathic pain by being dissolvedor suspended in either water or hydroxypropyl methylcellulose,respectively. Postoperative animals between 14 to 42 days were fastedovernight prior to dosing. Animals were orally dosed and dosage volumeswere calculated on a 4 mL/kg basis.

Table 6 shows results as either the ED₅₀ or % MPE in the Chung Model forcertain compounds selected from Formula (I) and Formula (II). Theabbreviations used in the table have the following meanings: IA refersto “inactive at the sceening dose;” ED₅₀ refers to the “50% EffectiveDose” orally administered in mg per Kg (mpk). TABLE 6 Cpd ED₅₀ or % MPE1 ED₅₀ = 22 mpk 2   7% 3   5% 4 lA 5   9% 6  12% 7 ED₅₀ = 22 mpk 8 1.3%9   5% 10  11% 11  10% 12 3.7% 13 lA 15 7.9% 16 ED₅₀ = 29 mpk 17  59%

The results of the “Chung Model” study suggest that antiallodyniccompounds of the present invention may be effective in treating ormodulating neuropathic pain.

For treating or modulating neuropathic pain, a compound selected fromFormula (I) or Formula (II) should not have B selected from2-thienylcarbonyl attached to the pyrrole ring on the 2 position or1H-imidazol-5-ylcarbonyl attached to the pyrrole ring on the 4 position.

For treating or modulating neuropathic pain, a compound selected fromFormula (I) or Formula (11) may be employed at a daily dosage in therange of from about 30 to about 4000 mg, usually in 2 to 4 divideddoses, for an average adult human. A unit dose would contain from about10 to about 500 mg of the active ingredient. More generally, formammals, the treatment would comprise the daily administration of fromabout 0.001 mg/kg to about 500 mg/kg.

In particular, a pharmaceutical composition of the present inventioncomprising a pharmaceutically acceptable carrier and a compound selectedfrom Formula (I) or Formula (II) administered orally may be especiallysuitable for use in treating or modulating neuropathic pain.

The present invention includes a method for treating or modulatingneuropathic pain comprising internally administering to a subject inneed thereof a therapeutically effective amount of a compound selectedfrom Formula (I) or Formula (II) or a pharmaceutical compositionthereof.

BIOLOGICAL EXAMPLE 5

Procedure for Testing Hyperalgesic Effect

The procedure used to detect the antihyperalgesic activity of a compoundof the present invention for which there is a good correlation withhuman efficacy is the Carrageenan Paw Hyperalgesia Test (as described inSammons, et al., Brain Research, 2000, 876, 48-54).

Animals

Male, CD-1 mice (Charles River Laboratories) weighing 22-30 g each atthe time of testing are housed in a climate-controlled, virus freeenvironment for at least 7 days prior to testing. Food and water areavailable ad libitum up to test time.

Animal Dosing

Test mice are immunized by injecting an irritant (e.g., 0.02 mL of a1.0% carrageenan solution in 0.9% saline) subcutaneously into thesubplantar tissue of one of the hind paws to stimulate an acuteinflammatory reaction. The response of the animal following carrageenaninjection is subsequently evaluated at a fixed later time and verifiedto be hyperalgesic relative to a baseline response obtained immediatelyprior to carrageenan injection.

The mice were dosed orally with either Compound 1 dissolved in asuspension of 20% hydroxypropyl beta cyclodextrin in distilled water orwith vehicle alone at a fixed time following carrageenan injection. Thedosing volume was 10 mL/kg. Response latencies were subsequentlyevaluated at fixed times following oral dosing to assess reversal ofhyperalgesia caused by treatment with Compound 1 as compared to vehicletreatment.

Measurement of Hyperalgesia

Hyperalgesia is assessed by measurement of a response to a thermalstimulus. Measurement of thermal hyperalgesia is made with a standardlaboratory hot plate apparatus, whose surface temperature is preciselydetermined and evenly maintained. Alternatively, hyperalgesia isevaluated with a commercially available Hargreaves apparatus whichselectively elevates the temperature of an individual paw (Dirig, etal., J. Neurosci. Methods, 1997, 76, 183). A response is defined as anyshaking, licking, or tucking of the treated paw. With either apparatus,hyperalgesia is defined as a reduced latency to response compared to thebaseline latency recorded prior to carrageenan injection and theantihyperalgesic effect of the test compound is seen as a (partial)restoration of the latency toward normal (Dirig, et al., J. Pharmacol.Expt. Therap., 1998, 285,1031).

The reversal of hyperalgesia produced by therapeutic intervention isexpressed as a percent recovery (% R), that is, a percentage of the fullreversal possible, taking into account individual differences inbaseline response latencies and the severity of post carrageenanhyperalgesia as assessed prior to therapeutic intervention.

The % Recovery (% R) by a compound tested was calculated according tothe formula:% R=100×[(PDL−PCL)/(BL−PCL)];wherein PDL is defined as Post Drug Latency, PCL is Post CarrageenanLatency and BL is Baseline Latency.

The results in the Carrageenan Paw Model for Compound 1 orallyadministered at 30 mg per Kg demonstrates a % Recovery of 84% comparedto a vehicle control % Recovery of 12% when each group was assessed at90 minutes following oral dosing.

The results in the Carrageenan Paw Model suggest that compounds of thepresent invention may be effective as antihyperalgesic agents intreating or modulating pain associated with inflammation or aninflammatory-related disorder.

For treating or modulating inflammation or an inflammatory-relateddisorder, a compound selected from Formula (I) or Formula (II) may beemployed at a daily dosage in the range of from about 30 to about 4000mg, usually in 2 to 4 divided doses, for an average adult human. A unitdose would contain from about 10 to about 500 mg of the activeingredient. More generally, for mammals, the treatment would comprisethe daily administration of from about 0.001 mg/kg to about 500 mg/kg.

In particular, a pharmaceutical composition of the present inventioncomprising a pharmaceutically acceptable carrier and a compound selectedfrom Formula (I) or Formula (II) administered orally may be especiallysuitable for use in treating or modulating inflammation or aninflammatory-related disorder.

The present invention includes a method for treating or modulatinginflammation or an inflammatory-related disorder comprising internallyadministering to a subject in need thereof a therapeutically effectiveamount of a compound selected from Formula (I) or Formula (II) or apharmaceutical composition thereof.

BIOLOGICAL EXAMPLE 6

Procedure for Testing Antiinflammatory Response

The procedure used to detect the antiinflammatory activity of a compoundof the present invention for which there is a good correlation withhuman efficacy is the Carrageenan Paw Edema Model (as described in Levy,L., Carrageenan Paw Edema in the Mouse, Life Sci., 1969, 8,11, 601-6).

Animals

Male, Sprague-Dawley rats (Charles River Laboratories) 175-200 g arehoused in a climate-controlled, virus free environment for at least 5days prior to testing.

Procedure

Carrageenan is prepared in saline (0.5% carrageenan solution in 0.9%saline) and injected in a 0.1 mL volume into the footpad of the rat.Test compound is administered orally by gavage 30-60 minutes prior tofootpad challenge. Paws are dipped into a mercury plethysmograph edemacomputer (Buxco Electronics) and the foot displacement is recorded at 0time and at various times after challenge with carrageenan. Rats treatedwith test compound are compared to vehicle controls for any inhibitionof carrageenan induced paw swelling.

The % Inhibition (% I) by a compound tested was calculated according tothe formula:% I=100−[100×(TCPV/VCPV)];wherein TCPV is defined as the mean Change in Paw Volume in the Treatedgroup and VCPV is the mean Change in Paw Volume in the Vehicle group.

Rats treated with Compound I at a dose of 100 mg/kg, p.o., exhibited a35% inhibition of carrageenan-induced paw swelling at 2 hours postcarrageenan administration. The results in the Paw Edema Model suggestthat compounds of the present invention may be effective asantiinflammatory agents in treating or modulating inflammation or aninflammatory-related disorder.

For treating or modulating inflammation or an inflammatory-relateddisorder, a compound selected from Formula (I) or Formula (II) may beemployed at a daily dosage in the range of from about 30 to about 4000mg, usually in 2 to 4 divided doses, for an average adult human. A unitdose would contain from about 10 to about 500 mg of the activeingredient. More generally, for mammals, the treatment would comprisethe daily administration of from about 0.001 mg/kg to about 500 mg/kg.

In particular, a pharmaceutical composition of the present inventioncomprising a pharmaceutically acceptable carrier and a compound selectedfrom Formula (I) or Formula (II) administered orally may be especiallysuitable for use in treating or modulating inflammation or aninflammatory-related disorder.

The present invention includes a method for treating or modulatinginflammation or an inflammatory-related disorder comprising internallyadministering to a subject in need thereof a therapeutically effectiveamount of a compound selected from Formula (I) or Formula (II) or apharmaceutical composition thereof.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1-32. (canceled)
 33. A method for treating or modulating a centralnervous system disorder comprising administering to a subject in needthereof a therapeutically effective amount of a compound selected fromFormula (I) or Formula (II):

wherein A is selected from the group consisting of phenvl andnaphthalenyl optionally substituted with 1 to 4 substituents; B isselected from heteroaryl optionally substituted on 1 to 4 availablecarbon atom ring members with a substituent selected from the groupconsisting of halogen, C₁₋₈alkyl C₁₋₈alkoxy, hydroxy,hvdroxy(C₁₋₈)alkyl, hydroxy(C₁₋₈)alkoxy, (halo)₁₋₃C₁₋₈)alkyl and(halo)₁₋₃(C₁₋₈)alkoxy; and, optionally substituted on available nitrogenatom ring members with a substituent selected from the group consistingof C₁₋₈alkyl, C₂₋₈alkyl, hydroxy(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkyl andoxido; Z is selected from the group consisting of oxo and hydroxy; R¹ isselected from the group consisting of: C₁₋₈alkyl {wherein alkyl isoptionally substituted on a terminal carbon with one substituentselected from the group consistinr of C₁₋₈alkoxy, —C(O)— (substitutedwith one substituent selected from the group consisting of H, OH,C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂), —NHC(O)—(substituted with one substituent selected from the group consisting ofH, OH, C₁₋₈alkyl, C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂),—OC(O)— (substituted with one substituent selected from the groupconsisting of H, OH, C₁₋₈alkyl, C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl,—N((C₁₋₈ alkyl)₂), NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂, —S(C₁₋₈)alkyl,—SO₂(C₁₋₈)alkyl, cyano, (halo)₁₋₃, hydroxy and nitro}, cycloalkyl andaryl {wherein cycloalkyl and aryl are optionalIv substituted with 1 to 4substituents independently selected from the group consisting of cyano,halo. hydroxy and nitro; and, wherein cycloalkyl and aryl are optionallysubstituted with one substituent selected from the group consisting ofC₁₋₈alkyl, (wherein alkyl is optionally substituted on a terminal carbonwith one substituent selected from the group consisting of NH₂,—NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂, cyano, (halo)₁₋₃, hydroxy and nitro),C₁₋₈akoxy, NH₂, —NH(C₁₋₈)alkyl and —N((C₁₋₈)alkyl)₂}; R² and R³ areindependently selected from the group consisting of hydrogen, C₁₋₈alkyland halogen; and pharmaceutically acceptable acid addition salts.quaternary ammonium salts and N-oxides thereof.
 34. The method of claim33 wherein the central nervous system disorder is selected from thegroup consisting of neuropathic pain, chronic pain, pain, neurologicalconditions, cardiovascular diseases and other disorders, psychoticdisorders, movement disorders, anxiety disorders or neurodegenerativedisorders.
 35. The method of claim 34 wherein neuropathic pain isneuropathic pain resulting from chronic or debilitating conditions(selected from painful diabetic peripheral neuropathy, post-herpeticneuralgia, trigeminal neuralgia, post-stroke pain, multiplesclerosis-associated pain, neuropathies-associated pain (selected frompain as a result of idiopathic neuropathy, post-traumatic neuropathy ormononeuritis), HIV-associated neuropathic pain, cancer-associatedneuropathic pain, carpal tunnel-associated neuropathic pain, spinal cordinjury-associated pain, complex regional pain syndrome,fibromyalgia-associated neuropathic pain, lumbar and cervical pain,reflex sympathic dystrophy, phantom limb syndrome or other chronic anddebilitating condition associated pain syndromes), sympatheticallymaintained pain or cluster and migraine headache-associated pain; painassociated with cancer, fibromyalgia, back disorders or migraine andchronic headache, adiposis dolorosa and burn pain, central painconditions following stroke, thalamic lesions or multiple sclerosis orpain resulting from damage to the peripheral or central nervous system(selected from damage as a result of amputation, paraplegia, herpes oras a result of diabetic polyneuropathy).
 36. The method of claim 34wherein chronic pain is chronic pain resulting from inflammation or aninflammatory-related condition, osteoarthritis, rheumatoid arthritis oras sequela to disease, acute injury or trauma and is selected from thegroup consisting of upper back pain and lower back pain (as a result ofsystematic, regional or primary spine disease (such as radiculopathy),inflammation or an inflammatory-related condition), bone pain (as aresult of osteoarthritis, rheumatoid arthritis, osteoporosis or bonemetastases), pelvic pain, spinal cord injury-associated pain, cardiacchest pain, non-cardiac chest pain, central post-stroke pain, myofascialpain, cancer pain, AIDS-related pain, sickle cell pain, geriatric painor headache-associated pain (selected from chronic or migraineheadache), trigeminal neuralgia, temporomandibular joint syndrome,fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis, gout,fibrositis and thoracic outlet syndromes.
 37. The method of claim 34wherein neurological conditions are selected from the group consistingof anxiety, convulsions, cyclophrenia, hypotonia, epilepsy, bipolardisorder and unipolar depression.
 38. The method of claim 37 whereinepilepsy is selected from the group consisting of simple partialseizures, complex partial seizures, secondary generalised seizures andgeneralized seizures (selected from the group consisting of absenceseizures, myoclonic seizures, clonic seizures, tonic seizures, tonicclonic seizures and atonic seizures).
 39. The method of claim 37 whereinbipolar disorder is selected from the group consisting of bipolardisorder type I, bipolar disorder type II, cyclothymic disorder, rapidcycling, ultradian cycling, bipolar depression, acute mania, mania,mixed mania, hypomania and episodes associated with bipolar disorder.40. The method of claim 34 wherein cardiovascular diseases and otherdisorders are selected from the group consisting of arrhythmias(selected from cardiac arrhythmia, cardiac infarction or anginapectoris), hypertension, endocrine disorders (selected from acromegalyor diabetes insipidus), tinnitus, muscle spasm, urinary incontinence,diarrhea, pruritus, functional bowel disorders (selected from non-ulcerdyspepsia, non-cardiac chest pain or irritable bowel syndrome), muscularsclerosis, macular degeneration, glaucoma, diseases in which thepathophysiology of the disorder involves excessive or hypersecretory orotherwise inappropriate cellular secretion of an endogenous substance(such as a catecholamine, a hormone or a growth factor) and emesis. 41.The method of claim 34 wherein the therapeutically effective amount ofthe compound is from about 0.001 mg/kg/day to about 500 mg/kg/day. 42.The method of claim 34 further comprising a method for use of a thecompound as a local anesthetic for treating or modulating chronic paincomprising topically or subcutaneously administering to a subject inneed thereof a therapeutically effective amount of the compound.
 43. Themethod of claim 42 wherein the therapeutically effective amount of thecompound is from about 0.001 mg to about 500 mg.
 44. The method of claim42 further comprising a method for use of a compound of claim 1 as alocal anesthetic for prophylactically treating or modulating chronicpain comprising topically or subcutaneously administering to a subjectin need thereof a therapeutically effective amount of the compound. 45.The method of claim 33 wherein the aryl of A is phenyl optionallysubstituted with 1 to 4 substituents.
 46. A method for treating ormodulating a central nervous system disorder comprising administering toa subject in need thereof a therapeutically effective amount of acompound selected from Formula (I) or Formula (II):

wherein A is selected from the group consisting of thienyl, pyridinyl,quinolinyl and isoquinolinyl optionally substituted on 1 to 4 availablecarbon atom ring members with a substituent and optionally substitutedon available nitrogen atom ring members with a substituent; B isselected from heteroaryl optionally substituted on 1 to 4 availablecarbon atom ring members with a substituent selected from the groupconsisting of halogen, C₁₋₈alkyl, C₁₋₈alkoxy, hydroxy,hydroxy(C₁₋₈)alkyl, hydroxy(C₁₋₈)alkoxy, (halo)₁₋₃(C₁₋₈)alkyl and(halo)₁₋₃(C₁₋₈)alkoxy; and, optionally substituted on available nitrogenatom ring members with a substituent selected from the group consistingof C₁₋₈alkyl, C₂₋₈alkenyl, hydroxy(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkyl andoxido; Z is selected from the group consisting of oxo and hydroxy; R¹ isselected from the group consisting of: C₁₋₈alkyl {wherein alkyl isoptionally substituted on a terminal carbon with one substituentselected from the group consisting of C₁₋₈alkoxy, —C(O)— (substitutedwith one substituent selected from the group consisting of H, OH,C₁₋₈alkyl, C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂), —NHC(O)—(substituted with one substituent selected from the group consisting ofH, OH, C₁₋₈alkyl, C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂),—OC(O)— (substituted with one substituent selected from the groupconsisting of H, OH, C₁₋₈alkyl, C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl,—N((C₁₋₈)alkyl)₂), NH₂, —NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂, —S(C₁₋₈)alkyl,—SO₂(C₁₋₈)alkyl, cyano, (halo)₁₋₃, hydroxy and nitro}, cycloalkyl andaryl {wherein cycloalkyl and aryl are optionally substituted with 1 to 4substituents independently selected from the group consisting of cyano,halo, hydroxy and nitro; and, wherein cycloalkyl and aryl are optionallysubstituted with one substituent selected from the group consisting ofC₁₋₈alkyl, (wherein alkyl is optionally substituted on a terminal carbonwith one substituent selected from the group consisting of NH₂,—NH(C₁₋₈)alkyl, —N((C₁₋₈)alkyl)₂, cyano, (halo)₁₋₃, hydroxy and nitro),C₁₋₈alkoxy, NH₂, —NH(C₁₋₈)alkyl and —N((C₁₋₈)alkyl)₂}; R² and R³ areindependently selected from the group consisting of hydrogen, C₁₋₈alkyland halogen; and pharmaceutically acceptable acid addition salts,quaternary ammonium salts and N-oxides thereof.
 47. The method of claim46 wherein the heteroaryl of A is selected from the group consisting ofthienyl and pyridinyl optionally substituted on 1 to 4 available carbonatom ring members with a substituent and optionally substituted onavailable nitrogen atom ring members with a substituent.
 48. The methodof claim 47 wherein the central nervous system disorder is selected fromthe group consisting of neuropathic pain, chronic pain, pain,neurological conditions, cardiovascular diseases and other disorders,psychotic disorders, movement disorders, anxiety disorders orneurodegenerative disorders.
 49. The method of claim 47 whereinneuropathic pain is neuropathic pain resulting from chronic ordebilitating conditions (selected from painful diabetic peripheralneuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-strokepain, multiple sclerosis-associated pain, neuropathies-associated pain(selected from pain as a result of idiopathic neuropathy, post-traumaticneuropathy or mononeuritis), HIV-associated neuropathic pain,cancer-associated neuropathic pain, carpal tunnel-associated neuropathicpain, spinal cord injury-associated pain, complex regional painsyndrome, fibromyalgia-associated neuropathic pain, lumbar and cervicalpain, reflex sympathic dystrophy, phantom limb syndrome or other chronicand debilitating condition associated pain syndromes), sympatheticallymaintained pain or cluster and migraine headache-associated pain; painassociated with cancer, fibromyalgia, back disorders or migraine andchronic headache, adiposis dolorosa and burn pain, central painconditions following stroke, thalamic lesions or multiple sclerosis orpain resulting from damage to the peripheral or central nervous system(selected from damage as a result of amputation, paraplegia, herpes oras a result of diabetic polyneuropathy).
 50. The method of claim 47wherein chronic pain is chronic pain resulting from inflammation or aninflammatory-related condition, osteoarthritis, rheumatoid arthritis oras sequela to disease, acute injury or trauma and is selected from thegroup consisting of upper back pain and lower back pain (as a result ofsystematic, regional or primary spine disease (such as radiculopathy),inflammation or an inflammatory-related condition), bone pain (as aresult of osteoarthritis, rheumatoid arthritis, osteoporosis or bonemetastases), pelvic pain, spinal cord injury-associated pain, cardiacchest pain, non-cardiac chest pain, central post-stroke pain, myofascialpain, cancer pain, AIDS-related pain, sickle cell pain, geriatric painor headache-associated pain (selected from chronic or migraineheadache), trigeminal neuralgia, temporomandibular joint syndrome,fibromyalgia syndrome, osteoarthritis, rheumatoid arthritis, gout,fibrositis and thoracic outlet syndromes.
 51. The method of claim 47wherein the therapeutically effective amount of the compound is fromabout 0.001 mg/kg/day to about 500 mg/kg/day.